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date: 23 January 2020

Potassium Channels and Pain

Abstract and Keywords

The K+ channel family is one of the most complex families of ion channels. The diversity of this channel family is a real challenge for the study of pain. Potassium channels form the largest family of ion channels in mammals, with more than 80 genes encoding α subunits in humans. Their differences in structures and functions divide them into four families, all of which are expressed in somatosensory neurons and supporting glial cells. The opening of K+ channels hyperpolarizes the plasma membrane, which opposes excitation of the neuron by all other depolarizing channels. K+ channels are very efficient regulators of the electrical activity of sensory neurons and of pain perception. Their potential for the development of antinociceptive pharmacology is immense.

Keywords: potassium channels, voltage-gated potassium channels, two-pore domain background potassium channels, calcium-activated potassium channels, inwardly- rectifying potassium channels, hyperpolarization, antinociception, pain

The potassium channels family is the largest family of ion channels; it has a unique diversity of more than 80 genes coding for α subunits in humans (Coetzee et al., 1999). Differences in the structures and functional characteristics of α subunits define four large families of K+ channels in mammals: voltage-gated K+ (Kv) channels, two-pore domain background K+ (K2P) channels, Ca2+-activated K+ (KCa) channels, and inwardly rectifying K+ (Kir) channels.

Potassium channels are expressed in almost all cells of the body, where they are essential for the cellular homeostasis of K+, which plays a major role in many cellular processes, like cell volume regulation, proliferation, necrosis, and apoptosis. They are involved in all major neuronal functions and contribute to neuronal information coding. They limit the release of neurotransmitter and hormones. They control the generation, the shape, and the discharge frequency of action potentials. Of importance and a possible limitation to the development of novel analgesic modulators of K+ channels, they are involved in life-supporting physiological functions such as muscle contraction and maintenance of heart rate.

The K+ channels exert strong control over the polarity of the plasma membrane by selectively conducting the efflux of K+ through the membrane according to its electrochemical gradient. In neurons and other excitable cells, K+ is about 30 times more concentrated inside the cell than in the extracellular medium, which brings the equilibrium potential for K+ toward negative values near or below -80 mV. As a result, K+ permeability is hyperpolarizing inhibitory and opposes the depolarization of the plasma membrane by all other excitatory channels permeable to Na+, Ca2+, or nonselective to these cations. In dorsal root ganglion sensory neurons (DRG neurons), the intracellular concentration of chloride is usually very high, and its equilibrium potential is in the range of -25 to -40 mV (Alvarez-Leefmans, Gamino, Giraldez, & Nogueron, 1988). Cl- permeability is therefore depolarizing and in some conditions can be excitatory by bringing the membrane potential near the threshold potential for action potential firing, usually about -40 mV.

The somatosensory nervous system expresses all four families of K+ channels, which are active contributors to the electrical activity of sensory neurons (Figure 1). At rest, in anesthetized rats in vivo, the membrane potential of sensory DRG neurons, including nociceptive and non-nociceptive neurons, has been measured between -50 and -65 mV (Fang, McMullan, Lawson, & Djouhri, 2005). Background leak K+ (K2P), M-type K+ channels (Kv7 or KCNQ), and Kir channels are active at subthreshold membrane potential to maintain this level of resting membrane polarization. Sensory neurons encode the intensity, velocity, and duration of stimuli with trains of action potentials. For example, cutaneous mechanosensory fibers have slow, intermediate, fast, and ultrafast firing adaptation to encode mechanical stimuli (Delmas, Hao, & Rodat-Despoix, 2011). Kv and KCa channels are major determinants of firing adaptation because they speed the repolarization of the action potential and generate the after-hyperpolarization of the plasma membrane. Their role is defined by their voltage sensitivity, kinetics of activation and inactivation, and importantly by their regulation by intracellular messengers.

Potassium Channels and Pain

Figure 1. Phylogenetic tree of the different families of mammalian K+ channels. There are three main membrane topologies and degree of sequence homology with Kv (violet), KCa (red), Kir (blue), and K2P (yellow) channels. Bottom, an illustration of the role of K+ channel families in pain perception from the skin in the periphery to the central synapse in the spinal cord.

The K+ channel activity imposes the strongest endogenous brake on the excitability of sensory neurons. Many studies reported that inhibition of K+ channels may be just sufficient to trigger spontaneous firing of sensory neurons in the absence of sensory stimulation. These observations are relevant to the large body of evidence showing that downregulation of K+ channel expression is correlated with DRG neuron spontaneous activity and spontaneous pain in many chronic pathophysiological conditions. Recent studies have, for example, linked the inhibition of background K+ channels to the burning and tingling paresthesia sensations caused by otherwise-unrelated pungent substances like Szechuan pepper or pyrethroid insecticides (Bautista et al., 2008; Castellanos et al., 2018). Previous studies showed that application of the broad-spectrum Kv channel inhibitors tetraethylammonium (TEA) and 4-aminopyridine (4-AP) on rat DRG neurons induced continuous firing of nociceptive and non-nociceptive fibers (Burchiel & Russell, 1985; Kirchhoff, Leah, Jung, & Reeh, 1992). These early studies observed that cutaneous nerve endings and cell somata of DRG neurons had different sensitivity to TEA and 4-AP, thus implying that the expression of K+ channels varied significantly between cellular compartments. This makes the study of K+ channel function in pain sensation very complex (Ocana, Cendan, Cobos, Entrena, & Baeyens, 2004). We describe some of the many studies that involve all four families of K+ channels in somatosensory perception and pain.

Voltage-Gated Potassium Channels and Pain

The Kv channels are the largest family of K+ channels (Yellen, 2002). In humans, they are encoded by 40 different genes categorized into 12 subfamilies (Kv1 to Kv12) (Gutman et al., 2005), each of which has several members that are phylogenetically related to the Drosophila Shaker channel. All Kv channels are tetramers forming the ion conduction pore. Each α subunit has six transmembrane domains, including voltage-sensing (S1–S4) domains, pore (S5–S6) domains, and a variable C-terminal domain. The α subunits can bind to regulatory Kvβ subunits and Kv channel-interacting proteins, which strongly modify channel properties (Pongs & Schwarz, 2010). A family of modifier/silencer Kv channels (KvS; Kv5.1, Kv6.1 to 6.6; Kv8.1 and 8.2; Kv9.1 to 9.9) was not able to form functional channels despite sharing the typical topology of Kv channels (Bocksteins, 2016; Salinas, Duprat, Heurteaux, Hugnot, & Lazdunski, 1997). KvS silent subunits form heteromers with Kv2 subunits (Kv2.1 and Kv2.2), which can have significant physiological consequences. This diversity produces a wide spectrum of Kv channels with differing biophysical and pharmacological profiles.

Early electrophysiological characterization revealed six major types of Kv currents in DRG neurons (Gold, Shuster, & Levine, 1996). Three are transient A-type currents (IKA) with rapid activation and inactivation at high voltage that speeds action potential repolarization without affecting spike initiation and height. Decreased A-type currents have been linked to persistent pain sensitization (Zemel, Ritter, Covarrubias, & Muqeem, 2018). Mammalian A-type channels include Kv1.4, Kv3.3, Kv3.4, and Kv4.1–Kv4.3 subunits. Three of the Kv currents found in DRG neurons are delayed rectifier D-type currents (IKDR). D-type currents appear gradually after the ascending phase of the action potential and inactivate slowly. They participate in the repolarization phase and the refractory period between action potentials. They control the frequency of discharge. IKDR channels include Kv1.1, Kv1.2, Kv1.5, Kv1.6, Kv2.1, Kv2.2, Kv3.1, and Kv3.2 subunits (Sheng, Hong, Zhang, Zhang, & Zhang, 2018). Kv2.1 has an additional non-conducting role by facilitating vesicle release in neuroendocrine cells and DRG neurons through an association with syntaxin (Feinshreiber et al., 2010). Kv7/KCNQ channels (Kv7.1 to Kv7.5) are M-type channels that contribute to slow IKDR. They conduct very slow noninactivating K+ currents with thresholds for activation below -60 mV, so they are increasingly recognized as among the most important regulators of resting membrane potential and spike threshold in nociceptive neurons (Du, Gao, Jaffe, Zhang, & Gamper, 2018; Passmore et al., 2003).

Kv Expression in Sensory Neurons

The Kv channels are highly expressed in mouse and human DRG and trigeminal (TG) neurons (Flegel et al., 2015; Manteniotis et al., 2013; Rasband et al., 2001). The most abundantly expressed Kv1 subunits in rodent DRG neurons are Kv1.1, Kv1.2, and Kv1.4. Kv1.1 and Kv1.2 are predominant in large Aβ DRG neurons and high-threshold nociceptive C mechanoreceptors (Hao et al., 2013). They are not found in small-diameter C-nociceptive isolectin B4-positive (IB4) DRG neurons, where Kv1.4 is the main Kv1 subunit (Vydyanathan, Wu, Chen, & Pan, 2005).

The Kv2 channels and silent subunit KvS are expressed in mouse DRG neurons (Bocksteins et al., 2009). Kv2 is particularly abundant in medium-size Aδ and large neurons and more than half of the small-diameter nociceptive neurons (Tsantoulas et al., 2014). Kv3 is a high-threshold channel containing rapidly inactivating (Kv3.3 and Kv3.4) or slowly inactivating (Kv3.1 and Kv3.2) subunits. Kv3 channels are expressed in all DRG neurons (Chien, Cheng, Chu, Cheng, & Tsaur, 2007). Kv3.4 subunits appear to be especially enriched in small-diameter neurons positive for Nav1.8 and TRPV1 channels (transient receptor potential vanilloid type 1). Kv4 subunits are expressed at different levels in DRG neurons (Matsuyoshi et al., 2012). Kv4.1 is expressed in DRG neurons of all sizes. Kv4.2 is absent from small-diameter neurons, while Kv4.3 is mainly found in a subset of nonpeptidergic nociceptive DRG neurons, coexpressing Nav1.8 and TRPV1.

M-type Kv7.2, Kv7.3, and Kv7.5 channels are expressed in DRG neurons, with Kv7.2 and Kv7.3 the predominant subunits (King & Scherer, 2012; Roza, Castillejo, & Lopez-Garcia, 2011). However, the expression of these channels suffers from controversy. Abundant expression of Kv7.2 was found in small-diameter nociceptive DRG neurons (Passmore et al., 2012; Rose et al., 2011). Others found some expression of Kv7.2 in large non-nociceptive neurons, while small-diameter nociceptive DRG neurons would express predominantly Kv7.5 (King & Scherer, 2012). The reasons for this discrepancy are yet to be identified; however, the pharmacological profile of M currents recorded from nociceptive DRG neurons argues against a strong contribution of Kv7.5 (Linley, Pettinger, Huang, & Gamper, 2012).

Kv Channels and Pain

Because Kv activity opposes membrane depolarization and action potential generation, Kv channels generally inhibit sensory neuron excitability. Indeed, reductions in Kv expression and activity appear to be a hallmark of the hyperexcitability seen in many pain syndromes resulting from traumatic nerve injuries, painful diabetic neuropathy, anticancer chemotherapy-induced neuropathy, visceral pain, or bone cancer pain (Table 1). A minority of studies, however, also reported increased expression of Kv channels in chemotherapy-induced neuropathy or bone cancer pain.

Table 1 Kv channels expression in peripheral sensory neurons

K+ Channel Family

Subunit

Species

Assay

Commentary

References

Kv

KCNA1 (Kv1.1)

Rat DRG

Rat DRG

Mouse DRG

Rat DRG

Mouse DRG

Mouse DRG and TG

Human DRG and TG

Rat and human myelinated axons in DRG

IH

RT-PCR

IC, IH

RT-PCR

qPCR

RNAseq

RNAseq

IH, WB

Predominantly in large neurons; reduced by nerve injury (SNL)

Transient decreased expression by injury (CCI)

Ab mechanoreceptors and C high-threshold mechanoreceptors

Decreased expression after axotomy

Decreased expression by 4 days oxaliplatin-induced neuropathy

Decreased expression at the neuroma after nerve injury

Rasband et al., 2001

Kim et al., 2002

Hao et al., 2013

Yang et al., 2004

Descoeur et al., 2011

Manteniotis et al., 2013

Flegel et al., 2015

Calvo et al., 2016

KCNA2 (Kv1.2)

Rat DRG

Rat DRG

Rat DRG

Rat DRG

Mouse DRG and TG

Rat DRG

Mouse DRG

Mouse DRG

Rat DRG

Mouse DRG

Human DRG and TG

Rat and human myelinated axons in DRG

IH

RT-PCR

RT-PCR

q-PCR

RNAseq

Multiple-gene RT-PCR array

RT-PCR

RT-PCR

IH, WB

RT-PCR

RNAseq

IH, WB

Predominantly in large neurons; reduced by nerve injury (SNL)

Decreased expression by injury (CCI)

Decreased expression after axotomy

Large neurons, reduced by injury (SNL) through endogenous antisense RNA

Increased after paclitaxel-induced neuropathy

Epigenetic silencing of Kcna2 in the axotomized DRG

Epigenetic silencing of Kcna2 in DRG from neuropathic mice

Decreased in injured DRG (CCI)

Epigenetic silencing of Kcna2 following nerve injury (SNL)

Decreased expression at the neuroma after nerve injury

Rasband et al., 2001

Kim et al., 2002

Yang et al., 2004

X. Zhao et al., 2013

Manteniotis et al., 2013

H. Zhang & Dougherty, 2014

Liang et al., 2016

Zhao et al., 2017

Yuan et al., 2019

Mo et al., 2018

Flegel et al., 2015

Calvo et al., 2016

KCNA4 (Kv1.4)

Rat DRG

Rat DRG

Rat DRG

Rat DRG

Rat DRG

Rat DRG

Mouse DRG and TG

Rat DRG

Human DRG and TG

Rat and human DRG

IH

RT-PCR

RT-PCR

IC

RT-PCR

IH, WB

RNAseq

RT-PCR

RNAseq

IH, WB

Predominantly in small neurons; reduced by nerve injury (SNL)

Decreased expression by injury (CCI)

Decreased expression after axotomy

Mainly in IB4(+) neurons

Decreased expression in diabetic rats

Increased in IB4(+) neurons from bone cancer pain

Nerve injury (SNL) gradually decreased expression level of KCNQ2

Increased expression at the neuroma after nerve injury; myelinated axons

Rasband et al., 2001

Kim et al., 2002

Yang et al., 2004

Vydyanathan et al., 2005

Cao et al., 2010

Duan et al., 2012

Manteniotis et al., 2013

Laumet et al., 2015

Flegel et al., 2015

Calvo et al., 2016

KCNA6 (Kv1.6)

Human DRG and TG

Rat and human myelinated axons in DRG

RNAseq

IH, WB

Increased expression at the neuroma after nerve injury

Flegel et al., 2015

Calvo et al., 2016

KCNA10 (Kv1.8)

Human DRG and TG

RNAseq

Flegel et al., 2015

KCNB1 (Kv2.1)

Mouse DRG

Rat DRG

Rat DRG

RT-PCR, IHC

ISH, IHC

ISH, qPCR

Small and large neurons; reduced by nerve injury

Bocksteins et al., 2009

Tsantoulas et al., 2012

Tsantoulas et al., 2014

KCNB2 (Kv2.2)

Rat DRG

Mouse DRG

Rat DRG

Mouse DRG

Mouse DRG and TG

Human DRG and TG

α-Galactosidase A–deficient mice DRG

RT-PCR

RT-PCR, IHC

ISH, qPCR

RNAseq

RNAseq

RNAseq

MicroRNA

Decreased expression by injury (CCI)

Small and large neurons; reduced by nerve injury

Decreased expression in L4 DRG neurons from SNL mouse

Decreased expression as compared with wild-type littermates

Kim et al., 2002

Bocksteins et al., 2009

Tsantoulas et al., 2014

S. Wu et al., 2016

Manteniotis et al., 2013

Flegel et al., 2015

Kummer, Kalpachidou, Kress, & Langeslag, 2018

KCNC1 (Kv3.1)

Rat DRG

RT-PCR

Kim et al., 2002

KCNC2 (Kv3.2)

Rat DRG

Mouse DRG and TG

RT-PCR

RNAseq

Kim et al., 2002

Manteniotis et al., 2013

KCNC4 (Kv3.4)

Rat DRG

Rat DRG

Rat DRG

IH

RT-PCR

IH, WB

Mainly in C fibers; reduced by nerve injury

Decreased expression in diabetic rats

Decreased in neurons from bone cancer pain

Chien et al., 2007

Cao et al., 2010

Duan et al., 2012

KCND1 (Kv4.1)

Rat DRG

Rat DRG

Mouse DRG and TG

Human DRG and TG

RT-PCR

IHC, ISH, RT-PCR

RNAseq

RNAseq

Expression in DRG neurons of various sizes

Kim et al., 2002

Matsuyoshi et al., 2012

Manteniotis et al., 2013

Flegel et al., 2015

KCND2 (Kv4.2)

Rat DRG

Rat DRG

Rat DRG

Rat DRG

RT-PCR

IH, RT-PCR

RT-PCR

RT-PCR

Decreased expression by injury (CCI)

Very low expression

Decreased expression in diabetic rats

Nerve injury (SNL) gradually decreased expression level of KCNQ2

Kim et al., 2002

Phuket & Covarrubias 2009

Cao et al., 2010

Laumet et al., 2015

KCND3 (Kv4.3)

Rat DRG

Rat DRG

Rat DRG

Rat DRG

Rat DRG

Mouse DRG and TG

Rat TG

RT-PCR

IH

RT-PCR

IH, WB

IHC, ISH, RT-PCR

RNAseq

IH

Decreased expression by injury (CCI)

Cell bodies of nonpeptidergic neurons; reduction by injury linked to mechanical hypersensitivity

Decreased expression in diabetic rats

Increased in IB4(+) neurons from bone cancer pain

Predominantly in small-size C-fiber neurons

Decreased expression in oxaliplatin-treated rats

Kim et al., 2002

Chien et al., 2007

Cao et al., 2010

Duan et al., 2012

Matsuyoshi et al., 2012

Manteniotis et al., 2013

Viatchenko-Karpinski, Ling, & Gu, 2018

KCNE3

α-Galactosidase A–deficient mice DRG

MicroRNA

Increased expression as compared with wild-type littermates

Kummer et al., 2018

KCNG1 (Kv6.1)

Mouse DRG

RT-PCR

Bocksteins et al., 2009

KCNG2 (Kv6.2)

Mouse DRG and TG

RNAseq

Manteniotis et al., 2013

KCNG3 (Kv6.3)

Mouse DRG

Mouse DRG and TG

Human DRG and TG

RNAseq

RNAseq

RNAseq

Decreased expression in L4 DRG neurons from SNL mouse

S. Wu et al., 2016

Manteniotis et al., 2013

Flegel et al., 2015

KCNG4 (Kv6.4)

Mouse DRG

Human DRG and TG

RNAseq

RNAseq

Decreased expression in L4 DRG neurons from SNL mouse

S. Wu et al., 2016

Flegel et al., 2015

KCNQ2 (Kv7.2)

Rat DRG

Rat and mouse peripheral nerves

Rat DRG

Mouse peripheral nerves

Rat peripheral nerves

Rat DRG

Mouse fiber endings and DRG neurons

Rat DRG

Rat TG

Rat TG

Rat DRG

RT-PCR, IC

IH, WB

IH

IH

IHC

IH, WB

IH

RT-PCR

IH

IH

RT-PCR, WB

Small and large neurons

Nodes of Ranvier

Expressed in small-diameter nociceptive neurons; decreased expression following neuropathic injury

Accumulated in neuromas

Expressed in the peripheral terminals of nociceptive primary afferents

Decreased expression in a model of bone cancer pain

Axotomy enhances axonal transport in injured sensory neurons

Nerve injury (SNL) gradually decreased expression level

Decreased after oxaliplatin-induced neuropathy

Increased after nerve injury (ION-CCI)

Decreased after diabetic induction

Passmore et al., 2003

Devaux, Kleopa, Cooper, & Scherer, 2004

Rose et al., 2011

Roza et al., 2011

Passmore et al., 2012

Zheng et al., 2013

Cisneros, Roza, Jackson, &

Lopez-Garcia, 2015

Laumet et al., 2015

Ling, Erol, Viatchenko-Karpinski, Kanda, & Gu, 2017

Ling, Erol, & Gu, 2018

Yu et al., 2018

KCNQ3 (Kv7.3)

Rat DRG

Mouse and rat peripheral nerves

Rat DRG

Mouse and human colon

Rat DRG

Mouse DRG and TG

RT-PCR, IC

IH, WB

IH, qPCR

RT-PCR, WB

RNAseq

Small and large neurons

In paranodes and Lanterman incisures

Prominent decrease in expression in a bone cancer pain model

Expression in mouse and human colonic afferents

Decreased expression after diabetic induction

Passmore et al., 2003

Devaux et al., 2004

Zheng et al., 2013

Peiris et al., 2017

Yu et al., 2018

Manteniotis et al., 2013

KCNQ4 (Kv7.4)

Rat DRG

Mouse DRG

Mouse DRG and TG

RT-PCR, IC

IH

RNAseq

Specifically expressed in a defined subpopulation of cutaneous mechanoreceptors

Passmore et al., 2003

Heidenreich et al., 2011

Manteniotis et al., 2013

KCNQ5 (Kv7.5)

Rat DRG

Rat primary afferents

Mouse and human colon

Rat DRG

RT-PCR, IC

IH

IH, qPCR

RT-PCR, WB

Small and large DRG neurons

Main subunit expressed in C fibers

Expression in mouse and human colonic afferents

Decreased expression after diabetic induction

Passmore et al., 2003

King & Scherer 2012

Peiris et al., 2017

Yu et al., 2018

KCNV1 (Kv8.1)

Mouse DRG

Mouse DRG

Mouse DRG and TG

RT-PCR

RNAseq

RNAseq

Decreased expression in L4 DRG neurons from SNL mouse

Bocksteins et al., 2009

S. Wu et al., 2016

Manteniotis et al., 2013

KCNS1 (Kv9.1)

Mouse DRG

Rat DRG

Mouse DRG

Mouse DRG

Mouse DRG and TG

RT-PCR

ISH, IH, qPCR

RNAseq

IH

RNAseq

Expressed in myelinated neurons; reduced by injury; linked to spontaneous and evoked excitability and mechanical pain

Decreased expression in L4 DRG neurons from SNL mouse

Predominantly expressed in myelinated sensory neurons; after neuropathic injury, cKO mice develop greater mechanical pain

Bocksteins et al., 2009

Tsantoulas et al., 2012

S. Wu et al., 2016

Tsantoulas et al., 2018

Manteniotis et al., 2013

KCNS2 (Kv9.2)

Mouse DRG

RT-PCR

Bocksteins et al., 2009

KCNS3 (Kv9.3)

Mouse DRG

Mouse DRG and TG

RT-PCR

RNAseq

Bocksteins et al., 2009

Manteniotis et al., 2013

KCNH1 (Kv10.1)

Mouse DRG and TG

RNAseq

Manteniotis et al., 2013

KCNH5 (Kv10.2)

Mouse DRG and TG

RNAseq

Manteniotis et al., 2013

KCNH2 (Kv11.1)

Mouse DRG and TG

RNAseq

Manteniotis et al., 2013

KCNH6 (Kv11.2)

Mouse DRG and TG

Human DRG and TG

RNAseq

RNAseq

Manteniotis et al., 2013

Flegel et al., 2015

KCNH7 (Kv11.3)

Mouse DRG and TG

Rat DRG

RNAseq

Multiple-gene RT-PCR array

Increased after paclitaxel-induced neuropathy

Manteniotis et al., 2013

H. Zhang && Dougherty, 2014

KCNH8 (Kv12.1)

Mouse DRG and TG

RNAseq

Manteniotis et al., 2013

CCI = chronic constriction injury; cKO = conditional knock-out; IC = immunocytochemistry; IH = immunohistochemistry; ION-CCI = infra-orbital nerve chronic constriction injury; ISH = in situ hybridization; qPCR = quantitative transcription–polymerase chain reaction; RNAseq = RNA sequencing; RT-PCR = reverse transcription–polymerase chain reaction; SNL = spinal nerve ligation; WB = western blotting.

A-Type Kv Channels in Pain

Kv1.4 subunit expression in DRG neurons was significantly reduced by inflammation and neuropathy (Rasband et al., 2001; Zemel et al., 2018). In diabetic rats, brain-derived neurotrophic factor (BDNF) reduced the expression of Kv1.4, while treatment with anti-BDNF antibodies restored Kv1.4 currents and transcripts (Cao, Chen, Li, & Pan, 2012). Knockdown of Kv1.4 induced mechanical allodynia and eliminated the analgesic effects of diclofenac in bone cancer (Duan et al., 2012). Conversely, Kv1.4 may be implicated in compensatory mechanisms after nerve injury because its expression was upregulated in the juxtaparanodal regions of myelinated axons following nerve transaction, where both Kv1.1 and Kv1.2 expression was reduced (Calvo et al., 2016). This opposing regulation replaced a delayed rectifier current by a transient A-type current, which would increase neurons excitability.

Kv3.4 expression was reduced in both neuropathic pain and bone cancer pain models (Chien et al., 2007; Duan et al., 2012). Intrathecal injection of antisense Kv3.4 oligonucleotides induced mechanical hypersensitivity in rats (Chien et al., 2007). Conversely, in a diabetic model of neuropathy, Kv3.4 messenger RNA (mRNA) expression was increased in the entire DRG (Cao, Byun, Chen, Cai, & Pan, 2010). The reason for such a discrepancy is unclear.

Kv4.3 has been involved in mechanical allodynia phenotypes. Knockdown of Kv4.3 channels in DRGs induced mechanical allodynia (Chien et al., 2007; Conner, Alvarez, Bogen, & Levine, 2016). Expression of Kv4.2 and Kv4.3 was reduced in DRG neurons of neuropathic or axotomized rats (Kim, Choi, Rim, & Cho, 2002; Park et al., 2003). Diabetic neuropathy also correlated with a decrease in Kv4 currents in nociceptors (Cao et al., 2010; Grabauskas et al., 2011). In models of irritable bowel syndrome, inactivation of Kv4.2 by mitogen-activated protein kinase (MAPK) correlated with depolarized resting membrane potential and increased excitability of sensory neurons (A. H. Qian et al., 2009; Xu, Wu, Grabauskas, & Owyang, 2013). Conversely, Kv4.3 expression increased in a model of bone cancer pain (Duan et al., 2012). Kv4.3 may have a neuroprotective role in dampening excitability in cancer pain because inactivation of Kv4.3 blocks the ability of diclofenac to reverse cancer-induced mechanical allodynia (Duan et al., 2012).

Non–A-Type Kv Channel Involvement in Pain

Kv1.1 has intrinsic mechanosensitivity (Hao et al., 2013). Kv1.1–Kv1.2 heteromers produce a mechanosensitive K+ current (IKmech) that governs firing adaptation in rapidly adapting Aβ fibers and increases mechanical thresholds in C nociceptive fibers (Hao et al., 2013). Peripheral nerve injury leads to Kv1.1 and Kv1.2 downregulation (Calvo et al., 2016; Z. Li et al., 2015; X. Zhao et al., 2013). A decrease of the IKD current carried by Kv1.1 and Kv1.2 has also been implicated in cold hypersensitivity and cold allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in mice (Madrid, de la Pena, Donovan-Rodriguez, Belmonte, & Viana, 2009; Viana, de la Pena, & Belmonte, 2002). Even if Kv1 subunits are not temperature sensitive, these studies suggest that IKD carried by Kv1 plays a protective role against cold allodynia by increasing the cold sensitivity threshold of nociceptive DRG neurons expressing transient receptor potential melastatin 8 (TRPM8). Consistently, KV1.1 expression is downregulated by oxaliplatin injection, a drug used in anticancer therapy that is often associated with cold allodynia (Descoeur et al., 2011). Kv2.1 makes a significant contribution to peripheral excitability. Indeed, inhibition of Kv2.1 increases sensory neuron excitability by allowing greater fidelity of repeated firing during sustained input. A decrease in neuronal expression of Kv2.1 has been correlated with neuropathic pain following nerve injury (Ishikawa, Tanaka, Black, & Waxman, 1999). Interestingly, the expression of the silent Kv9.1 subunit associated with Kv2.1 in large- and medium-size DRG neurons is also downregulated following nerve injury, which coincides with the emergence of pain behaviors (Costigan et al., 2010; Ishikawa et al., 1999). This was further confirmed with Kv9.1 knockout mice, which showed increased acute and neuropathic pain phenotypes (Tsantoulas et al., 2018). Kv9.1 polymorphisms were also associated with the risk of developing phantom limb pain and low-back pain in humans (Costigan et al., 2010). Kv2.1 was also found in the majority of nociceptive C fibers, and although Kv9.1 was absent from these fibers, other KvS could possibly modulate Kv2.1 in these neurons.

M-type Kv7 currents strongly contribute to sensory fibers’ excitability in humans (Lang, Fleckenstein, Passmore, Brown, & Grafe, 2008; Peiris et al., 2017). Specific pharmacology for Kv7 channels is available and of potential interest for analgesia. Opening Kv7 channels produced hyperpolarization and reduced neuronal excitability, whereas the closure of the channel produced opposite effects (Du et al., 2018; Linley, Ooi, et al., 2012). Intraplantar injection of the M-channel blocker XE991 into the hind paw of rats induced moderate pain, while peripheral injection of M-channel openers such as retigabine and flupirtine produced an analgesic effect. Kv7 channels are involved in nociceptive mechanoperception and inflammatory pain (Heidenreich et al., 2011; King, Lancaster, Salomon, Peles, & Scherer, 2014; B. Liu et al., 2010). A marked decreased activity of Kv7.2 and Kv7.3 channels were observed in DRG neurons in models of neuropathic pain and bone cancer pain (Zheng et al., 2013). M-channel openers retigabine and flupirtine reduced hyperexcitability of both DRG and spinal neurons and alleviated neuropathic pain or bone cancer pain (Cai et al., 2015; Rose et al., 2011). This suggests that despite the downregulation of M-channel activity, opening endogenous Kv7 channels in DRG neurons may be a good strategy to alleviate pain.

K2P Channels

The family of K2P K+ channels has 15 members grouped into six subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK) based on sequence and functional similarities (Enyedi & Czirjak, 2010). They were initially named according to their functional properties. The first K2P channel cloned was TWIK1, for tandem of pore domains in a weak inward-rectifying K+ channel (Fink et al., 1996). Other members of the TWIK family are TWIK2 and KCNK7 (K2P7.1). The TREK (TWIK-related K+ channel) subfamily contains TREK1, TREK2, and TRAAK (TWIK-related arachidonic acid activated K+) channels. This subfamily is activated by arachidonic acid, polyunsaturated fatty acids (PUFAs), volatile anesthetics, and pain-related stimuli (Noel, Sandoz, & Lesage, 2011). The TASK (TWIK-related acid-sensitive K+ channel) subfamily contains TASK1, TASK3, and TASK5 (K2P15.1, KCNK15). This subfamily is inhibited by extracellular acidification. The TALK (TWIK-related alkaline pH-activated channel) subfamily includes TALK1, TALK2 (K2P17.1, KCNK17), and TASK2, which have an important sensitivity to extracellular alkaline pH. The THIK (tandem pore domain halothane-inhibited K+) channel subfamily has THIK1 and THIK2. Their main feature is inhibition by halothane. The TRESK (TWIK-related spinal cord K+) subfamily channel has only one member, TRESK with low similarity to other K2P channels. It is the only K2P regulated by intracellular Ca2+ via activation of the phosphatase calcineurin.

In contrast to other K+ channels that have one pore-forming domain for each subunit, K2P channels have two pore domains and four transmembrane domains. Functional K2P channels are dimers. K2P channel activity produces constitutive leak currents independent of the membrane potential. They influence neuronal excitability over a wide range of membrane potentials, especially between resting and action potential threshold. Thus, K2P channels are one of the main sustained K+ conductance that establish the resting membrane potential of DRG neurons. They can also shape the duration, frequency, and amplitude of the action potential.

K2P Channel Expression in Sensory Neurons

Almost all K2P channels are expressed in DRG and TG neurons (Table 2). Nevertheless, the relative expression of each channel varies between different neuronal populations and species. In humans, the most prevalent channels in DRG and TG are THIK-2, TASK1, and TWIK1, followed by TREK1, TASK2, and TRESK (Flegel et al., 2015). Other studies found TRESK as the most expressed channel in human TG (Lafreniere et al., 2010; LaPaglia et al., 2017; Medhurst et al., 2001). In mouse and rat sensory neurons, TRESK, TRAAK, TREK2, TREK1, TWIK1, and TWIK2 are the most highly expressed channels, although relative expression may vary between studies (Acosta et al., 2014; Dobler et al., 2007; Manteniotis et al., 2013; Marsh, Acosta, Djouhri, & Lawson, 2012; Morenilla-Palao et al., 2014; Pollema-Mays, Centeno, Ashford, Apkarian, & Martina, 2013; Talley, Solorzano, Lei, Kim, & Bayliss, 2001).

Table 2 K2P Channels Localization and Expression in Peripheral and Spinal Cord Sensory Neurons

K+ Channel Family

Subunit

Species

Assays

Commentaries

References

K2P

KCNK1 (TWIK1) (K2P1.1)

Rat and mouse DRG

Rat L4/L5 DRG

Rat L4 DRG

Human DRG

Rat DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

IH

IH

RT-PCR, WB

RT-PCR

Multiple-gene RT-PCR array

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

Restricted expression level

Robust expression in large- and medium-size neurons. No overlap with TRPV1 or Ib4. Robust and persistent decrease by neuropathic injury

Decreased expression in ipsilateral L4 DRG. A rescue approach attenuated SNL-induced pain

Decreased after paclitaxel-induced neuropathy

Highest expression among the K2P channels

High expression

Mainly in parvalbumin-positive touch and proprioreceptors

High expression in GABAergic neurons

Talley et al., 2001

Pollema-Mays et al., 2013

Mao et al., 2017

Medhurst et al., 2001

H. Zhang & Dougherty, 2014

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015; Chiu et al., 2014

Häring et al., 2018

KCNK2 (TREK1) (K2P2.1)

Mouse DRG

Rat and mouse DRG

Mouse DRG

Rat DRG

Mouse DRG

Rat TG (31%)

Rat DRG

Rat DRG

Mouse DRG

Mouse DRG

Mouse DRG and TG

Mouse DRG

Rat DRG

Rat L5 DRG

Human DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

IC

IH

IH, IC

RT-PCR

RT-PCR

IH

qPCR

RT-PCR

qPCR

Single cell RT-PCR

RT-PCR

RNAseq

RT-PCR

RT-PCR

IH

RT-PCR

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

Small- and medium-size DRG neurons

Limited expression levels

Small nociceptive C fibers, overlap with TRPV1 expression

Medium expression

Overlap with TRPV1, TRPM8 expression

Expression unaltered by axotomy

Medium expression unaltered by 4 days of inflammation

Decreased expression at 4 days after oxaliplatin-induced neuropathy

DRG neurons innervating the colon

Decreased expression 2 days after TNBS-induced colitis

DRG neurons innervating the prostate

Increased expression in thoracolumbar and lumbosacral neurons after prostate inflammation

Downregulated in damaged versus contralateral sensory neurons

Expression found in vagal afferent neurons from the stomach or duodenum

Strong immunoreactivity of TREK1 channels, mainly in small-size L5 rat DRG neurons

Higher expression in mouse than humans

Mainly in peptidergic and nonpeptidergic nociceptors

Broad expression in glutamatergic and GABAergic neurons

Maingret, Lauritzen et al., 2000

Talley et al., 2001

Alloui et al., 2006

Kang & Kim, 2006

Dobler et al., 2007

Yamamoto et al., 2009

Tulleuda et al., 2011

Marsh et al., 2012

Descoeur et al., 2011

La & Gebhart, 2011

Schwartz, Xie, La, & Gebhart, 2015

Manteniotis et al., 2013

Reinhold et al., 2015

H. Zhao, Sprunger, & Simasko, 2010

Viatchenko-Karpinski et al., 2018

Medhurst et al., 2001

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015; Chiu et al., 2014

Häring et al., 2018

KCNK3 (TASK1) (K2P3.1)

Rat and mouse DRGs

Rat DRG

Rat DRG

Mouse DRG

Mouse DRG and TG

Mouse DRG and TG

Rat DRG

Small rat DRGs

Rat DRG

Human DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

IH

IC

RT-PCR

RT-PCR

RNAseq

RT-PCR

RT-PCR

qPCR

RT-PCR

RT-PCR

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

High expression levels

Low expression

Inhibition by pungent agents from Szechuan peppers

Expression unaltered by axotomy

Low expression unaltered by inflammation

after 4 days

Overlap with TRPV1. Unaltered by neuropathic injury (SNL)

Highest expression among the K2P channels

Similar expression in mouse and humans

Expressed mainly in peptidergic nociceptors

Broad expression in glutamatergic and GABAergic neurons

Talley et al., 2001

Rau, Cooper, & Johnson, 2006

Kang & Kim, 2006

Dobler et al., 2007

Manteniotis et al., 2013

Bautista et al., 2008

Tulleuda et al., 2011

Marsh et al., 2012

Pollema-Mays et al., 2013

Medhurst et al., 2001

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015

Häring et al., 2018

KCNK4 (TRAAK) (K2P4.1)

Rat and mouse DRGs

Rat DRG

Colon DRG neurons

Mouse DRG

Rat TG (60%)

Mouse DRG

Mouse DRG

Rat DRG

Rat L5 DRG

Rat DRG

Human DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

IH

RT-PCR

RT-PCR

IH

qPCR

RT-PCR

IH

qPCR

RT-PCR

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

High expression levels

Low expression level

Expression overlap with TRPV1, TRPM8

Expressed together with thermo-TRP channels in sensory neurons

Decreased expression at 4 days by oxaliplatin-induced neuropathy

Expression unaltered by axotomy

Strong immunoreactivity, mainly in small-size L5 rat DRG neurons

High expression unaltered by inflammation after 4 days

Higher expression in mouse than humans

Expression in peptidergic and nonpeptidergic nociceptors and low-threshold mechanoreceptors

Low expression found preferentially in GABAergic neurons

Talley et al., 2001

Kang & Kim, 2006

Dobler et al., 2007

Yamamoto et al., 2009

Noel et al., 2009

Descoeur et al., 2011

Tulleuda et al., 2011

Viatchenko-Karpinski et al., 2018

Marsh et al., 2012

Medhurst et al., 2001

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015; Chiu et al., 2014

Häring et al., 2018

KCNK5 (TASK2) (K2P5.1)

Rat and mouse DRGs

Rat DRG

Mouse DRG

Rat DRG

Human DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

IH

IC

qPCR

qPCR, IC

RT-PCR

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

High expression levels

Low expression level

Low expression, further decreased by inflammation after 4 days

Significant expression in mouse, low in humans

Low expression

No or low expression

Talley et al., 2001

Rau et al., 2006

Dobler et al., 2007

Marsh et al., 2012

Medhurst et al., 2001

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015

Häring et al., 2018

KCNK6 (TWIK2) (K2P6.1)

Rat DRG

Mouse DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

qPCR

RNAseq

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

Expression unaltered by inflammation after 4 days

Increased expression in L4 DRG neurons from SNL mouse

Low expression

Low expression

No or low expression

Marsh et al., 2012

S. Wu et al., 2016

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015

Häring et al., 2018

KCNK9 (TASK3) (K2P9.1)

Rat and mouse DRGs

Rat DRG

Rat DRG

Mouse DRG

Rat DRG

Small (C-fiber) rat DRGs

Mouse DRG and TG

Mouse DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

IH

RT-PCR

IC

RT-PCR

RT-PCR

IH

RT-PCR

RT-PCR, IC

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

Limited expression levels

Limited expression

Low expression decreased further by inflammation after 4 days

No overlap of expression with TRPV1 or IB4. Expression unaltered by neuropathic injury

Inhibition by pungent agents from Szechuan peppers

Highly enriched expression in TRPM8-positive neurons

Low expression in mouse but higher in humans

No expression

No or low expression

Talley et al., 2001

Kang & Kim, 2006

Rau et al., 2006

Dobler et al., 2007

Marsh et al., 2012

Pollema-Mays et al., 2013

Bautista et al., 2008

Morenilla-Palao et al., 2014

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015

Häring et al., 2018

KCNK10 (TREK2)

(K2P10.1)

Rat and mouse DRGs

Rat DRG

Rat TG (43%)

Rat DRG

Rat DRG

Small (C-fiber) rat DRGs

Mouse DRG

Prostate DRG

Rat L5 DRG

Human DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

IH

RT-PCR

IH

RT-PCR

RT-PCR

IC

qPCR

qPCR

IH

RT-PCR

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

Limited expression

Expression overlap with TRPV1, TRPM8 in DRG neurons

Expression unaltered by axotomy

High expression unaltered by 4 days of inflammation

Expression overlap with IB4, decreased by axotomy

Involvement in cold and warm thermosensation and pain perception. Decreased expression by 4 days of oxaliplatin-induced neuropathy

Increased expression in thoracolumbar neurons after prostate inflammation

Strong immunoreactivity, mainly in small-size L5 rat DRG neurons

Low expression in humans, higher in mouse

Mainly in peptidergic and nonpeptidergic nociceptors

Broad expression in glutamatergic and GABAergic neurons

Talley et al., 2001

Kang & Kim, 2006

Yamamoto et al., 2009

Tulleuda et al., 2011

Marsh et al., 2012

Acosta et al., 2014

Pereira et al., 2014

Schwartz et al., 2015

Viatchenko-Karpinski et al., 2018

Medhurst et al., 2001

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015; Chiu et al., 2014

Häring et al., 2018

KCNK12 (THIK2) (K2P12.1)

Rat DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

qPCR

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

Decreased expression at 1 day of inflammation but expression unaltered by 4 days

Highest mean transcript levels among the K2P family

High expression level

Low expression, mainly in nonpeptidergic nociceptors

No or low expression

Marsh et al., 2012

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015; Chiu et al., 2014

Häring et al., 2018

KCNK13 (THIK1) (K2P13.1)

Rat DRG (RT-PCR)

Mouse DRG

α-Galactosidase A–deficient mice DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

qPCR

RNAseq

MicroRNA

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

Low expression unaltered by 4 days of inflammation

Increased expression in L4 DRG neurons from SNL mouse

Increased expression as compared with wild-type littermates

Higher in mouse than humans

Mainly in peptidergic and nonpeptidergic nociceptors

No or low expression

Marsh et al., 2012

S. Wu et al., 2016

Kummer et al., 2018

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015; Chiu et al., 2014

Häring et al., 2018

KCNK16 (TALK1) (K2P16.1)

Mouse DRG

Mouse DRG

Human DRG and TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

RT-PCR

RNAseq

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

Low expression

Increased expression in L4 DRG neurons after SNL

Low or no expression

Very low expression

Low expression

No or low expression

Dobler et al., 2007

S. Wu et al., 2016

Flegel et al., 2015

Ray et al., 2018

Usoskin et al., 2015

Häring et al., 2018

KCNK18 (TRESK)

(K2P18.1)

Rat DRG

Mouse DRG

Rat small and medium DRG

Rat DRG

Mouse DRG and TG

Rat DRG (RT-PCR)

Mouse DRG and TG

Mouse DRG

Mouse DRG

Human and mouse DRG and TG

Human DRG and TG

Rat DRG

Human TG

Human and mouse DRG

Mouse DRG

Mouse dorsal horn spinal cord

RT-PCR

RT-PCR, IH

IH

RT-PCR

RT-PCR

RT-PCR

RNAseq

RNAseq

IC, WB, Ephys

RT-PCR, IH, IC

RNAseq

RT-PCR, IH, WB

RNAseq

RNAseq

Single-cell RNAseq

Single-cell RNAseq

High expression

High expression

Expression decreased by axotomy

Inhibition by pungent agents from Szechuan peppers

High expression unaltered by 4 days of inflammation

Decreased expression in L4 DRG neurons from SNL mouse

In primary DRG neurons the excitatory effect of LPA was shown to be balanced by coactivation of TRESK channels

High expression

Tumor-secreted VEGF activates a negative-feedback pathway through which TRESK expression was repressed in a rat model of bone metastatic breast cancer

Selective neural expression within two specific populations of ganglionic neurons

Similar expression in mouse and humans

Mainly in nonpeptidergic nociceptors and in a population of low-threshold mechanoreceptors

No or low expression

Kang & Kim, 2006

Dobler et al., 2007

Yoo et al., 2009

Tulleuda et al., 2011

Bautista et al., 2008

Marsh et al., 2012

Manteniotis et al., 2013

S. Wu et al., 2016

Kollert et al., 2015

Lafreniere et al., 2010

Flegel et al., 2015

Yang et al., 2018

Lapaglia et al., 2017

Ray et al., 2018

Usoskin et al., 2015; Chiu et al., 2014

Häring et al., 2018

Ephys = electrophysiology; IC = immunocytochemistry; IH = immunohistochemistry; LPA = lysophosphatidic acid; qPCR = quantitative transcription–polymerase chain reaction; RNAseq = RNA sequencing; RT-PCR = reverse transcriptase polymerase chain reaction; SNL = spinal nerve ligation; TNBS = 2,4,6trinitrobenzene sulfonic acid; VEGF = vascular endothelial growth factor; WB = western blotting.

Functional studies have identified TRESK, TREK2, TREK1, and TRAAK as the main background K+ currents in small- and medium-diameter DRG neurons (Acosta et al., 2014; Alloui et al., 2006; Kang & Kim, 2006). TWIK1 seems restricted to large- and medium-diameter DRG neurons (Pollema-Mays et al., 2013). THIK1, THIK2, and TRESK are mainly expressed in a single population of low-threshold mechanoreceptors and in IB4+ sensory neurons involved in pain and itch. TASK3 appears to be significantly expressed in TRPM8-positive cold thermoreceptors, which also showed some expression of TREK1 (Morenilla-Palao et al., 2014).

K2P channels are also expressed in neuronal populations of dorsal horn spinal cord neurons. A recent characterization of mRNA transcripts at the single-cell level has shown that TREK1, TWIK1, TREK2, and TRAAK are the predominant K2P channels in these neurons (Haring et al., 2018). All the other K2P channels were undetected or at very low levels of expression. Surprisingly, despite the initial cloning of TRESK from human spinal cord (Sano et al., 2003), this channel was not detected in the mice dorsal horn.

K2P Channels and Pain

Probably the most studied K2P channels belong to the subfamily of TREK channels. They were the first K2P channels initially involved in pain signaling (Alloui et al., 2006). TREK channels are highly regulated by biophysical stimuli relevant to somatosensory perception and nociception. Their activity is low in basal conditions, but they are potently activated by negative membrane stretch, temperature, intracellular or extracellular pH, and PUFAs (Honore, Maingret, Lazdunski, & Patel, 2002; Lesage, Maingret, & Lazdunski, 2000; Maingret, Lauritzen, et al., 2000; Maingret, Patel, Lesage, Lazdunski, & Honore, 2000; Noel et al., 2011; Patel et al., 1998; Sandoz, Douguet, Chatelain, Lazdunski, & Lesage, 2009).

Knockout mice lacking TREK channels have mechanical allodynia (Alloui et al., 2006; Noel et al., 2009; Pereira et al., 2014). It is reasonable to propose that the balance between mechanoactivation of TREK and activation of mechanosensitive excitatory cationic channels determines the threshold for mechanical activation of nociceptors. In the absence of TREK channels, the balance will be shifted toward activation, thus lowering threshold values. A nonspecific effect due to removal of K+ channels has been also hypothesized but seems unlikely because sensitization to osmotic stimuli by prostaglandin E2 (PGE2) is only lost when deleting TREK1 and TREK2 but not after deleting TRAAK. This may result from the regulation of TREK1 and TREK2, but not TRAAK, by G protein–coupled receptors (GPCRs).

TREK channels have steep thermosensitivity (Kang, Choe, & Kim, 2005; Maingret, Lauritzen, et al., 2000). TREK knockout mice have heat hypersensitivity from warm to noxious heat temperatures, a range of temperature where these channels are largely active (Alloui et al., 2006; Noel et al., 2009; Pereira et al., 2014). The response to heat of cutaneous nociceptive fibers is higher in the knockout mice, suggesting that TREK channels prevent activation of heat nociceptors.

TREK2 appears not to be involved in the detection of noxious heat but rather participates in the detection of less extreme warm temperatures. TREK2 channel seems to be necessary for the proper discrimination between warm perception and aversive noxious heat; thus in the absence of TREK2, temperatures that are not noxious are perceived as aversive (Pereira et al., 2014).

TREK channels also appear to be involved in setting the level of cold sensation. This is probably due to the reduction of channel activity at low temperatures. Again, TREK2 seems to be more involved in the control of the detection of moderate cool temperatures rather than noxious cold (Pereira et al., 2014). TREK1 and TRAAK channels are more important for sensation of aversive extreme cold and hot temperatures, whereas TREK2 regulates the perception of innocuous moderate cool and warm.

Altogether, these channels prevent the activation of thermonociceptive C fibers at moderate temperatures, therefore inhibiting pain sensation at nonnoxious temperatures. In models of peripheral inflammation, TREK2 expression was downregulated in IB4+ DRG neurons after paw inflammation (Acosta et al., 2014). This was correlated with increased spontaneous pain. In the same line, visceral inflammation reduced TREK1 and TREK2 expression in DRG neurons innervating the colon, which may contribute to colonic mechanohypersensitivity (La & Gebhart, 2011).

The role of TREK channels in neuropathic pain is less clear. Depending on the model of neuropathy used, results varied from downregulation (Reinhold et al., 2015) to no change in expression (Tulleuda et al., 2011). Nerve injury reduced TREK2 expression at the cell membrane in small DRG neurons, which was correlated with membrane depolarization and spontaneous firing (Acosta et al., 2014). Oxaliplatin chemotherapy-induced neuropathy was shown to decrease the expression of K+ channels TREK and Kv1.1, which contribute to cold hypersensitivity and hyperexcitability of peripheral fibers in mice (Descoeur et al., 2011). The sensitivity to cold of TREK knockout mice did not change after oxaliplatin treatment, which suggests that these channels are involved in the development of cold hypersensitivity by oxaliplatin. The mechanism for the downregulation of TREK channels is unknown.

TREK1 is involved in the analgesic effect of morphine acting on μOR (Devilliers et al., 2013). Analgesia induced by low doses of morphine was significantly reduced in the absence of TREK1. This identified TREK1 as a potential target for the treatment of pain avoiding the adverse side effects associated with opioids.

TRESK is involved in the regulation of nociceptive neuronal excitability after nerve injury (Tulleuda et al., 2011). In contrast to the TREK subfamily, although TRESK does not seem directly gated by mechanical stimuli, it is modulated by changes in membrane tension, and mice lacking TRESK show mechanical allodynia and lower mechanical thresholds for a large number of nociceptive fibers (Callejo, Giblin, & Gasull, 2013; Castellanos et al., 2018; X. Gasull, personal communication). Accordingly, intrathecal injection of small interfering RNA (siRNA) against TRESK produces an increase in mechanical sensitivity but does not modify the thermal sensitivity to radiant heat. On the contrary, overexpression of TRESK channels via intrathecal delivery of adenovirus inhibited capsaicin-mediated release of substance P in DRGs and reduces the excitability of TG neurons (Guo & Cao, 2014; Zhou et al., 2012). TRESK is not activated by temperature, but mice lacking TRESK showed enhanced sensitivity to noxious cold, without any effect on the detection of hot temperatures (X. Gasull, personal communication). A detailed characterization of this effect is still lacking, but these data suggest that TRESK is specifically involved in the sensitivity to cold stimuli, probably preventing cold neurons to be activated at non-noxious tempered temperatures.

TRESK, TASK1, and TASK3 are inhibited by hydroxy-α-sanshool, a natural compound from Szechuan peppers (Bautista et al., 2008). Sanshool could activate sensory neurons by inhibiting K2P background channels, thus depolarizing the cell, which might be responsible for the tingling, numbing sensation. The tactile component may result from the activation of large-diameter, touch-sensitive fibers, whereas the pungent or irritant qualities may involve excitation of non-peptidergic, capsaicin-sensitive nociceptors. These studies suggest that tingling paresthesia elicited by sanshool is mediated by activation of mechanosensitive somatosensory neurons through inhibition of K2P channels, in particular TRESK channels. Numbing of the sensation of pain reported by sanshool might be mediated by desensitization of activated neurons. Isobutylalkenyl amide (IBA), a hydroxy-α-sanshool synthetic derivative, induces tingling sensations in humans. In rats, IBA inhibits TRESK current, activates nociceptive C-type fibers, and induces nocifensive behaviors and mechanical allodynia (Tulleuda et al., 2011).

The observation that a dominant-negative mutation in TRESK was associated with familial migraine with aura implicated this channel in migraine pain (Lafreniere et al., 2010; P. Liu et al., 2013). Surprisingly, other mutations that inactivate TRESK were not correlated with migraine (Andres-Enguix et al., 2012; Guo, Liu, Ren, & Cao, 2014). These inconsistencies have been recently resolved in a study reporting that the TRESK mutation F139WfsX24 produced a nonfunctional channel and a second protein fragment that coassembles with and inhibits TREK1 and TREK2 channels. This downregulation of TRESK, TREK1, and TREK2 increased trigeminal sensory neuron excitability, leading to a migraine-like phenotype in rodents (Royal et al., 2019). This showed that K2P channels can combine together to control sensory neuron excitability.

TRESK channels have also been involved in inflammatory pain. The expression of TRESK, TASK1, TASK2, TASK3, and THIK1 was downregulated while mRNAs expression levels of other K2Ps did not seem to be significantly altered after cutaneous inflammation in the rat (Marsh et al., 2012). TRESK knockout mice showed an enhanced mechanical and thermal hyperalgesia after inflammation. Because mechanical sensitivity was enhanced in the knockout mice, it is not clear if TRESK participated in mechanical sensitization of sensory neurons during inflammation.

It can be envisaged that some inflammatory mediators, such as lysophosphatidic acid (LPA; Kollert, Dombert, Doring, & Wischmeyer, 2015), serotonin, or histamine could activate TRESK. The LPA-induced increase in the standing outward current and sensory neuron excitability was lost in the TRESK knockout mice (Kollert et al., 2015). This would indicate that TRESK plays a significant role during inflammation.

Several compounds released during inflammation have been proposed to enhance TRESK current through its intracellular regulation by Ca2+ and calcineurin (Kang et al., 2008). Nevertheless, some receptors could exert opposite effects on TRESK by modulating TRESK interaction with membrane lipids and phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis (Giblin, Etayo, Castellanos, Andres-Bilbe, & Gasull, 2019). Altogether, the role of TRESK during inflammation is still not well understood. It has been proposed that calcineurin-inhibitor pain syndrome (CIPS) that occurs as a result of calcineurin inhibition by immunosuppressive drugs such as tacrolimus (FK506) or cyclosporin could be due to impaired modulation of TRESK current, which would increase neuronal excitability to enhance pain sensitivity (Smith, 2009). TRESK downregulation was a clear feature found after nerve injury. TRESK expression was significantly decreased by sciatic nerve injury, nerve axotomy, and nerve ligation or in cancer-associated pain (Tulleuda et al., 2011; S. Wu et al., 2016; Yang et al., 2018; Zhou, Yang, Zhong, & Wang, 2013).

Reports on other K2P channels are diverse. Upregulation of THIK1, TALK1, and TWIK2 has been found after spared nerve injury (S. Wu et al., 2016). TWIK1 expression was decreased after paclitaxel-induced neuropathy, spinal nerve ligation or spared nerve injury (Pollema-Mays et al., 2013; H. Zhang & Dougherty, 2014). Interestingly, some channels showed a transient decrease in expression, such as TASK3, which was downregulated after 1 week but recovered normal expression 2 weeks after nerve injury (Pollema-Mays et al., 2013). Transient changes in expression of some K2P channels might be responsible for the different reports showing contradictory results.

TASK3 is expressed in cold-sensitive DRG neurons expressing TRPM8. Despite the fact that TASK3 shows very modest temperature sensitivity, the sensitivity of TRPM8 sensory neurons to cold or to TRPM8 agonists was enhanced in the absence of TASK3 (Morenilla-Palao et al., 2014). This suggests that TASK3 can be acting as a brake in excitability, dampening the sensitivity to cold temperatures of high-threshold, cold-sensitive nociceptive neurons.

In summary, K2Ps seem to have a significant role in modulating sensory neuron excitability during inflammation and neuropathic pain. Decreases in the expression of several K2P channels contributed to enhanced excitability after nerve injury or after chemotherapy-induced neuropathies, with some channels (e.g., TREK1, TREK2, TRAAK, and TRESK) having a major role. It has been reasoned that an activator of the TREK channel family, such as riluzole, could reverse the negative effects of oxaliplatin or nerve injury by restoring the initial level of channel activity. Indeed, riluzole acting on TREK1 prevented both the sensory and motor deficits induced by oxaliplatin as well as the depression-like phenotype induced by cumulative chemotherapeutic drug doses. TREK1 appeared to play a central role in riluzole therapeutic action (Poupon et al., 2018).

Calcium-Sensitive K+ Channels and Pain

The KCa family of K+ channels has eight members that are characterized by their dependence on intracellular calcium (Berkefeld, Fakler, & Schulte, 2010; Kaczmarek et al., 2017). They are activated by an increase in intracellular calcium concentration ([Ca2+]i) or voltage. Activated very quickly during depolarization, they participate in the repolarization of the spikes and limit the influx of Ca2+ by either disabling voltage-sensitive calcium channels or increasing the activity of Na+/Ca2+ exchangers. They reduced the amplitude and duration of transient calcium signals and the activation of downstream signaling pathways dependent on the [Ca2+]i. Thus, activation of KCa currents had a neuroprotective effect.

The KCa channels generate three types of potassium currents characterized by their unitary conductance. Voltage-dependent KCa currents are generated by big conductance KCa channels (BKCa) also called MaxiK due to their large conductance (between 100 and 300 picoSiemens). BKCa channels are formed by the tetrameric association of KCa1.1 (also called Slo1), KCa4.1 and 4.2 (also called Slack and Slick or Slo2.2 and Slo2.1 respectively), and KCa5.1 (Slo3) subunits. IBKCa currents are triggered by depolarization of the membrane regardless of the internal calcium concentration. However, an increase in [Ca2+]i (~10 μM) shifts the activation threshold of these channels to more hyperpolarized negative values, making them more easily activated from resting membrane potential.

KCa4.1 and 4.2 channels are a separate class of channels called KNa channels because they are activated by an increase in intracellular Na+ or Cl- (Bhattacharjee & Kaczmarek, 2005). BKCa1.1 and BKCa5.1 channels have a particular architecture that is different from other potassium channels. Indeed, they do not have six, but seven transmembrane domains. The main α subunits of BKCa channels are associated with auxiliary β subunits (BKCaβ), which changes the activity of these channels by modulation of their sensitivity to either Ca2+ or potential. BKCa participates in the rapid phase of repolarization after the action potential (fast afterhyperpolarization, fast IAHP) and contribute to spiking adaptation.

KCa currents activated by intracellular calcium and independent of potential are IKCa and ISKCa. They are produced by KCa2.1, 2.2, and 2.3 and KCa3.1 subunits, also named SK1 to SK4. ISKCa currents are produced by small conductance SKCa channels (between 2 and 20 pS), while IKCa currents are produced by intermediate conductance channels formed by KCa3.1 (SK4; between 20 and 100 pS). SK channels are not activated by a direct interaction with Ca2+ but by intracellular calmodulin (CaM) constitutively bound to the C-terminus domain of the channel that serves as a Ca2+ sensor (Keen et al., 1999). Interestingly, SK2 channels are present in the inner mitochondrial membrane, where they prevent the release of proapoptotic proteins (Dolga et al., 2013). SK channels regulate NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase function, thus hampering neuronal damage by preventing production of reactive oxygen species (ROS) in mitochondria (Fay, Qian, Jan, & Jan, 2006). SKCa currents participate in the slow phase of hyperpolarization following the action potential (slow afterhyperpolarization), regulate spike-frequency adaptation, and are powerful regulators of synaptic transmission (Petersen & Maruyama, 1984).

A large proportion of KCa currents in nociceptive DRG neurons is carried by BK channels, but both voltage-sensitive and -insensitive KCa channels are active in myelinated and unmyelinated DRG neurons (Bahia et al., 2005; W. Li et al., 2007) (Table 3). They are found in all cellular compartments of the neurons. KCa currents are important modulators of inflammatory and neuropathic pain. They are downregulated by nerve injury and inflammation, which induces nociceptive neuron hyperexcitability, ectopic firing, and spontaneous pain (Boettger et al., 2002; Cao et al., 2012; Laumet et al., 2015; Lu et al., 2014, 2015; Xing & Hu, 1999).

Several mechanisms may account for the decrease of KCa currents in painful conditions. KCa currents are depressed by neuromodulators like noradrenaline, which increases DRG neuron excitability by inhibition of SK2 channels (Honma, Yamakage, & Ninomiya, 1999). KCa channels are inhibited by pro-inflammatory lipids such as PGE2. Nerve injury releases neurotrophins, which modulate the activity of KCa currents. Injury decreases the expression of SK and IK currents in human DRG neurons, which can be compensated in vitro by nerve growth factor (NGF) (Boettger et al., 2002). Thus, in some painful conditions NGF may have a protective effect. However, nerve injury also increases the concentration of BDNF in the DRGs, which decreases BK currents in small- and medium-size neurons, a mechanism that could contribute to neuropathic pain (Cao et al., 2012).

Table 3 KCa Channels Localization and Expression in Peripheral Sensory Neurons

K+ Channel Family

Subunit

Species

Assays

Commentaries

References

BKCa

KCNMA1 (KCa1.1)

(BK)

(Slo1)

Rat DRG

Rat TG

Rat DRG

Rat DRG

Rat DRG

Mouse CGRP fibers

RT-PCR, IH, WB

RT-PCR, WB, IH

IC

CoIP

RT-PCR

Functional imaging

Decreased , primarily in small- and medium-size neurons, after nerve injury (SNL)

Uniquely expressed in unmyelinated C-type vagal afferents

TRPV1-BK coupling occurs in DRG cells

Nerve injury (SNL) gradually decreased expression level

Suppression of action potential firing by µOR activation is mediated by BK channels

Chen, Cai, & Pan, 2009

Wulf-Johansson et al., 2010

Li et al., 2011

Y. Wu et al., 2013

Laumet et al., 2015

Baillie, Schmidhammer, & Mulligan, 2015

KCNT1 (KCa4.1)

(Slack)

(Slo2.2)

Rat DRG

Rat DRG

Mouse DRG

Mouse DRG

α-Galactosidase A–deficient mice DRG

IH

IC

IH

IH

MicroRNA

Expressed in the small DRG neurons

Slack selectively controls the sensory input in neuropathic pain states

Decreased expression as compared with wild-type littermates

Tamsett, Picchione, & Bhattacharjee, 2009

Nuwer, Picchione, & Bhattacharjee, 2010

Huang et al., 2013

Lu et al., 2015

Kummer et al., 2018

KCNT2 (KCa4.2)

(Slick)

(Slo2.1)

Human DRG & TG

Mouse DRG

RNAseq

IH

Exclusively expressed in small- and medium-size CGRP(+) DRG neurons

Flegel et al., 2015

Tomasello, Hurley, Wrabetz, & Bhattacharjee, 2017

ISKCa

KCNN1 (KCa2.1)

(SKCa1)

Human DRG & peripheral nerves

Rat DRG

Mouse DRG

IH

IC

ISH, qPCR

Detected in a majority of large- and small-/medium-size cell bodies of hDRG; decreased in cell bodies of avulsed hDRG

Expression in NR1-positive DRG neurons

Boettger et al., 2002

Mongan et al., 2005

Pagadala et al., 2013

KCNN2 (KCa2.2)

(SKCa2)

Rat DRG

Mouse DRG

IC

ISH, qPCR

Expression in NR1-positive DRG neurons

Mongan et al., 2005

Pagadala et al., 2013

KCNN3 (KCa2.3)

(SKCa3)

Rat DRG

Rat DRG

IC

IC

Intense immunoreactivity in both C-type and A-type neurons

Mongan et al., 2005

Bahia et al., 2005

IKCa

KCNN4 (KCa3.1)

(IKCa1)

Human DRG & peripheral nerves

Rat DRG

Mouse DRG

IH

IC

IH

Detected in a majority of large- and small-/medium-size human DRG neurons

Expressed in most DRG satellite glial cells, and in a minority of DRG neurons

Boettger et al., 2002

Mongan et al., 2005

Lu et al., 2017

CGRP = calcitonin gene–related peptide; coIP = co-immunoprecipitation; hDRG = human dorsal root ganglion; IC = immunocytochemistry; IH = immunohistochemistry; ISH = in situ hybridization; NR1 = N-methyl-D-aspartate receptor (NMDAR) subunit 1; qPCR = quantitative transcription–polymerase chain reaction; RNAseq = RNA sequencing; RT-PCR = reverse transcriptase polymerase chain reaction; SNL = spinal nerve ligation; WB = western blotting.

KCa currents are unique modulators of sensory neuron excitability because they are activated by Ca2+, Na+, or Cl- influx, which is usually excitatory (Gueguinou et al., 2014). Indeed, increasing or restoring Ca2+ influx through the membrane of injured DRG neurons was shown to reduce hyperexcitability and spontaneous activity by increasing KCa currents (Hogan et al., 2008; Xing & Hu, 1999). TRPV1 is a heat-sensitive, Ca2+-permeable channel in nociceptive DRG neurons. Ca2+ influx through TRPV1 activates KCa1.1/Slo1 BK current (Y. Wu et al., 2013). This association forms a functional complex in which KCa1.1 activity opposes the excitatory depolarization by TRPV1. Interestingly, temperature sensing by TRPV1 showed steep voltage dependence (Voets et al., 2004), so it is possible that this cross activation of KCa1.1 by TRPV1 reduces heat activation of TRPV1. This could control the threshold for heat perception of nociceptive fibers expressing TRPV1.

In central neurons, NMDA receptors are Ca2+-permeable glutamate receptors involved in synaptic plasticity and excitotoxicity. NMDA receptors are essential for synaptic transmission of primary nociceptive afferences in the spinal cord. In nociceptive DRG neurons, gene deletion or pharmacological inhibition of NMDA receptors reduced Ca2+ influx and diminished SK1 and SK2 channel activity. This increased neuronal excitability and caused hypersensitivity to polymodal pain (Pagadala et al., 2013). Thus, unquestionably NMDA receptors are excitatory channels in central neurons, but they seem to have an unsuspected modulatory role in peripheral nociceptive DRG neurons via a functional interaction with SK channels. This unusual effect should be considered with attention when searching for therapeutic compound antagonists of central NMDA receptors.

These complex interactions between Ca2+ influx routes and KCa currents showed that the development of analgesic pharmacology aiming to antagonize excitatory receptors permeable to Ca2+ in peripheral DRG neurons could have paradoxical excitatory effects by indirect diminution of KCa currents. Conversely, these functional interactions between KCa channels and excitatory Ca2+ membrane permeabilities can have a strong antinociceptive potential. Measures to restore Ca2+ homeostasis in injured neurons may have therapeutic potential for peripheral neuropathic pain through the activation of KCa currents.

Finally, KCa channels have analgesic effects independent of channel activity and Ca2+ influx. BK is a competitive inhibitor for the binding of CaVα2δ subunit to CaV2.2 Ca2+ channels (F. X. Zhang, Gadotti, Souza, Chen, & Zamponi, 2018). The binding of BK channel to CaVα2δ opposes the expression of CaV2.2 at the cell membrane after nerve injury. This produces long-lasting analgesia against inflammatory and neuropathic pain. TMEM16C/ANO3 is a member of the anoctamin family of membrane proteins, expressed in the central and peripheral nervous systems of human, mouse, and rat. In rat IB4-positive nonpeptidergic nociceptive DRG neurons, TMEM16C binds to the KNa channel Slo2.2/Slack, which enhances KNa currents (Huang et al., 2013). The activation of KNa currents reduced the excitability of DRG neurons and thermal pain at high temperatures. This may contribute to the antinociceptive role described for KNa currents (Lu et al., 2015; Martinez-Espinosa et al., 2015).

KCa3.1/SK4 is strongly expressed in mice DRG satellite glial cells (SGCs) and in a minority of DRG neurons. Deletion of KCa3.1 in SGCs increased pain in models of formalin- and capsaicin-induced pain but had no effect on acute nociception, persistent inflammatory and neuropathic pain (Lu et al., 2017). Conversely, inhibition of KCa3.1 with senicapoc reversed mechanical allodynia in rats with peripheral nerve injury (Staal et al., 2017). The reason for this discrepancy is unclear, but this suggests that K+ homeostasis in SGCs contributes to the excitability of sensory neurons and the perception of pain. Interestingly, the phase II clinical trial for senicapoc revealed a significant increase of pain episodes among patients (Ataga et al., 2008). It must be emphasized that KCa inhibitors should be used with caution because they may cause pain episodes in certain conditions. Among K+ channels, the role of KCa channels in nociception is very complex, and the development of analgesic pharmacology targeting KCa currents is a real challenge that will need very careful design.

Inwardly Rectifying K+ Channels and Pain

The Kir channel subunits have only two transmembrane domains (M1 and M2) framing the pore domain (P). These two segments are homologous, respectively to the S5 and S6 domains of the Kv and KCa channels. Kir channels are open at all membrane potentials and do not have an inherent dependence on membrane potential (Hibino et al., 2010). Unlike voltage-dependent currents, they do not have an outward rectification, but they are characterized by a substantial entry of potassium at hyperpolarized potentials. Kir channels have limited outgoing currents for membrane potentials above the equilibrium potential for K+. So, initially referred to as “abnormal”, these channels are now referred to as inwardly rectifying K+ channels. This characteristic is the result of intracellular blockage by polyamines and magnesium (Mg2+). The voltage-dependent blockage literally clogs the pore of the channel, which limits outward K+ currents (IKir) but does not prevent inward currents. Under physiological conditions (i.e., above equilibrium potential for K+), however, it is the remaining low outward currents that contribute to the establishment and maintenance of the resting membrane potential. In neurons, Kir currents hyperpolarize the plasma membrane and reduce excitability. Presynaptic Kir channels directly control neurotransmitter release at the synapse.

The 15 members of this channel family have been classified into seven subfamilies, which are divided into four groups according to their regulation and associated proteins (Coetzee et al., 1999; Hibino et al., 2010; Kubo et al., 2005). The cytoplasmic N- and C-terminal domains, of variable length, are the sites of important regulation by G proteins, adenosine triphosphate (ATP), and membrane lipids. Unlike Kv currents, Kir currents are not sensitive to TEA or 4-AP. They are generally blocked by Ba2+ and Cs+ as well as alkaloid compounds such as quinine, quinidine, or chloroquine for Kir2 (Kurachi, Nakajima, & Sugimoto, 1987; Rodriguez-Menchaca et al., 2008). The Kir2 channels (Kir2.1 to Kir2.4) form a group of constitutively active channels with a marked inward rectification due to a high affinity for Mg2+ and intracellular polyamines.

The second group of Kir has four G protein–coupled inward rectifying channels (GIRK1 to 4, also named Kir3.1 to 3.4, respectively), which are opened by the binding of βγ subunits from trimeric G proteins to the intracellular domain of the channels. This family is activated by GPCRs like opioid receptors. They form homomers or heterotetramers, with the exception of GIRK1, which forms heteromers. To date, tertiapine isolated from bee venom is the only toxin specific to GIRK channels.

The Kir6.1 and Kir6.2 form the group of constitutively active KATP channels that are inhibited by ATP. These channels are sensors of the cell metabolic status. They open when the ratio ATP over ADP (adenosine diphosphate) decreases, which reduces the excitability of the cell. Their association with four sulfonylurea receptors (SURs) gives octomeric channels. SUR regulatory subunits permit membrane trafficking, sensitivity to ATP, as well as inhibition by the antidiabetic sulfonylureas such as glibenclamide (Zerangue, Schwappach, Jan, & Jan, 1999). Like the GIRK, KATP channels are also modulated by G protein βγ subunits (Wada et al., 2000).

A fourth group includes Kir channels (Kir1.1, Kir4.1 and 4.2, Kir5.1, and Kir7.1) activated by ATP or intracellular acidosis. Kir1.1 (also named ROMK) and Kir4.1 have an ATP-binding site in their C-terminal cytoplasmic domain. Kir4.1 forms heteromers with Kir5.1. Kir4.2 and Kir7.1 do not bind ATP, but they are sensitive to intracellular acidosis.

The antinociceptive role of Kir channels has been described in a number of studies (Table 4). The expression of Kir channels is expected to have a strong regulatory effect on sensory neuron excitability and nociception. Kir2.1 and Kir2.3 subunits are expressed in neuronal and glial cells in DRGs and spinal cord. Exogenous expression of Kir2.1 in DRG neurons reduces hyperexcitability and hyperalgesia caused by chronic compression of the ganglion (Ma, Rosenzweig, Zhang, Johns, & LaMotte, 2010). The expression of GIRK channels in DRG neurons is high in human and rat and low in mice (Gao, Zhang, You, Lu, & He, 2007; Manteniotis et al., 2013; Nockemann et al., 2013; Stotzner, Spahn, Celik, Labuz, & Machelska, 2018). Allele variation in the GIRK2 gene has been correlated with postoperative pain, acute and chronic low-back pain intensity, and sensitivity to opioid analgesia in humans (Bruehl et al., 2013; Nishizawa et al., 2009, 2014). In rat, the GIRK2 channel was necessary and sufficient to achieve peripheral opioid receptor-mediated analgesia (Nockemann et al., 2013). In mice, where GIRK2 is not expressed in DRG neurons, the exogenous expression of GIRK2 in nociceptive neurons provides opioid analgesia for inflammatory pain (Nockemann et al., 2013). This methodology is a good illustration of the potential interest of GIRK channel openers for the treatment of inflammatory pain (Bhave, Lonergan, Chauder, & Denton, 2010). GIRK1 and GIRK2 channels are important mediators of morphine-induced analgesia in the spinal cord. Studies using the GIRK channel inhibitor tertiapine and GIRK knockout mice demonstrated a role for these channels in the antinociceptive effect of µ and δ opioid receptors (Cruz et al., 2008; Ikeda, Kobayashi, Kumanishi, Niki, & Yano, 2000; Marker, Lujan, Loh, & Wickman, 2005; Marker, Stoffel, & Wickman, 2004; Yoshimura & North, 1983). GIRK1 and GIRK2 knockout mice have low analgesic responses to high doses of morphine injected in the spine. Notably, the analgesic response to low doses of morphine was preserved in the GIRK knockout mice, leaving the possibility for other K+ channels, like KATP and the K2P TREK-1 channels, to be involved in spinal morphine analgesia.

Table 4 Kir Channels Localization and Expression in Peripheral Sensory Neurons

K+ Channel Family

Subunit

Species

Assay

Commentaries

References

Kir2

KCNJ2 (Kir2.1)

Rat DRG

IHC

Most ganglionic neurons expressed Kir2.1

Murata, Yasaka, Takano, & Ishihara, 2016

KCNJ12 (Kir2.2)

Rat DRG

IHC

Most ganglionic neurons expressed Kir2.2

Murata et al., 2016

KCNJ4 (Kir2.3)

Human DRG

Rat DRG

Mouse DRG and TG

RT-PCR

IHC

RNAseq

Expressed in most ganglionic neurons and SGCs

Bauman et al., 2004

Murata et al., 2016

Manteniotis et al., 2013

KCNJ14 (Kir2.4)

Mouse DRG and TG

RNAseq

Manteniotis et al., 2013

GIRK

KCNJ3 (Kir3.1)

(GIRK1)

Rat DRG

Mouse DRG and TG

Mouse, human, and rat DRG

Rat DRG

Rat TG

Rat DRG

RT-PCR

RNAseq

RT-PCR, IH

Multiple-gene RT-PCR array

RT-PCR, WB, IH

IH, WB

Absent from mouse peripheral sensory neurons but present in human and rat

Increased after paclitaxel-induced neuropathy

Expressed mostly in nonpeptidergic afferents

Widely expressed in several sensory neuronal subtypes; decreased after peripheral axotomy

Gao et al., 2007

Manteniotis et al., 2013

Nockemann et al., 2013

H. Zhang & Dougherty, 2014

Chung et al., 2014

Lyu et al., 2015

KCNJ9 (Kir3.3)

(GIRK3)

Rat DRG

RT-PCR

Gao et al., 2007

KCNJ5 (Kir3.4)

(GIRK4)

Rat DRG

Rat DRG

RT-PCR

Multiple-gene RT-PCR array

Decreased after paclitaxel-induced neuropathy

Gao et al., 2007

H. Zhang & Dougherty, 2014

KCNJ6 (Kir3.2)

(GIRK2)

Rat DRG

Mouse, human, and rat DRG

Rat TG

Rat DRG

RT-PCR

RT-PCR, IH

RT-PCR, WB, IH

IH, WB

Absent from mouse peripheral sensory neurons but present in human and rat

Expressed mostly in nonpeptidergic afferents

Mainly expressed in a group of small C-fiber neurons; decreased after peripheral axotomy

Gao et al., 2007

Nockemann et al., 2013

Chung et al., 2014

Lyu et al., 2015

KATP

KCNJ8 (Kir6.1)

Rat DRG

Rat DRG

Rat DRG

Rat TG

Rat DRG

RT-PCR

IH

RT-PCR, IH, WB

RT-PCR, IH, WB

WB

High expression

Not found in DRG

Kir6.1 transcript, but not the protein, found in control DRG

Both transcript and protein expressed

Decreased expression around the incision site after skin/muscle incision and retraction

Kawabata et al., 2006

Kawano, Zoga, Gemes et al., 2009

Zoga et al., 2010

Niu, Saloman, Zhang, & Ro, 2011

L. P. Qian et al., 2016

KCNJ11 (Kir6.2)

Rat DRG

Rat DRG

Rat DRG

Rat TG

RT-PCR

IH

RT-PCT, IH, WB

RT-PCR, IH, WB

Low expression level

Channel activity identified in DRG neurons is suppressed in large compared to small neurons following nerve injury (SNL)

Kir6.2/SUR1 and Kir6.2/SUR2 channels expressed in rat DRG neuron somata, peripheral nerve fibers, and glial satellite and Schwann cells, in both normal state and after painful nerve injury (SNL)

Both transcript and protein expressed, higher in male than in female

Kawabata et al., 2006

Kawano, Zoga, Gemes et al., 2009

Zoga et al., 2010

Niu et al., 2011

Kir activated by ATP or acidosis

KCNJ1 (Kir1.1)

Rat DRG

Multiple-gene RT-PCR array

Decreased expression after paclitaxel-induced neuropathy

H. Zhang & Dougherty, 2014

KCNJ10 (Kir4.1)

Rat DRG and TG

Rat TG

Rat TG

Rat TG

Mouse DRG

IH, WB

IH, WB

IH

IH

qPCR, WB, IH

Expressed in SGCs; not expressed in neurons

Decreased expression following chronic constriction injury of the infraorbital nerve

Decreased expression in SGCs in inflamed rats

Coexpression with the GABAB receptor in SGCs from the TG

Decreased expression in SGCs from acute herpetic neuralgia

Vit et al., 2006

Vit et al., 2008

Takeda et al., 2011

Takeda, Nasu, Kanazawa, & Shimazu, 2015

Silva et al., 2017

IH = immunohistochemistry; IHC = in situ hybridization; qPCR = quantitative transcription–polymerase chain reaction; RNAseq = RNA sequencing; RT-PCR = reverse transcriptase polymerase chain reaction; SGC = satellite glial cell; SNL = spinal nerve ligation; WB = western blotting.

KATP channels Kir6.1 and Kir6.2 and their auxiliary subunits SUR1 and SUR2 are expressed in rodent DRGs (Manteniotis et al., 2013). There are some discrepancies between studies for the expression of Kir6.1 and Kir6.2 in large DRG neurons in rat (Chi, Jiang, & Nicol, 2007; Kawabata et al., 2006; Kawano, Zoga, Gemes, et al., 2009; Zoga et al., 2010). KATP inhibition by glibenclamide depolarized the resting membrane potential of large DRG neurons, while openers of KATP, such as diazoxide, hyperpolarized the plasma membrane and reduced DRG neurons excitability (Chi et al., 2007; Kawano, Zoga, McCallum, et al., 2009).

KATP channel openers diazoxide and pinacidil had an antinociceptive effect in various pain models, such as traumatic nerve injury, skin-muscle incision, or peripheral inflammation. The antinociceptive effect of KATP channel openers was preserved even though the expression of KATP channels in DRGs was decreased by traumatic nerve injury and inflammation, which, of course, could contribute to increase neuron excitability and pain perception in these conditions (Kawano, Zoga, Gemes, et al., 2009; L. P. Qian, Shen, Chen, Ji, & Cao, 2016; Zoga et al., 2010). This suggests that the remaining KATP currents are sufficient to dampen neuronal excitability in chronic pain conditions. Etidronate, a bisphosphonate used to treat osteoporosis, has an antiallodynic activity in arthritic rats through the activation of KATP channels (Kawabata et al., 2006). In the same line of evidence, peripheral analgesia by nonsteroidal anti-inflammatory drugs (NSAIDs) involved nitric oxide and cyclic guanosine monophosphate (cGMP) pathway opening KATP channels (Alves, Tatsuo, Leite, & Duarte, 2004; Chi et al., 2007; Gutierrez et al., 2012; Ortiz et al., 2012; Sachs, Cunha, & Ferreira, 2004).

KATP channels contributed to the antinociceptive effects of peripheral GPCRs alpha2-adrenoceptors and µORs and delta opioid-receptors (δORs) (Ocana & Baeyens, 1993; Ocana et al., 2004). However, they were not important for the antinociceptive effects of the kappa-opioid and gamma-aminobutyric acid B (GABAB) GPCR receptors (Ocana & Baeyens, 1993). The reason for this specificity is not clear. At the spinal cord level, KATP channels were involved in central antinociceptive activity of morphine acting on µOR (Ocana, Del Pozo, & Baeyens, 1993). Central intracerebroventricular injection of sulfonylureas dose-dependently antagonized the antinociceptive activity of morphine. This argues strongly for a role of KATP channels in central µOR-mediated analgesia. These behavioral measures of the antinociceptive actions of KATP channels downstream of µOR suggest that KATP channel activators could have the same potency as morphine without some of the side effects and complex regulations of µOR.

Kir4.1 was expressed in SGCs of TG (Vit, Jasmin, Bhargava, & Ohara, 2006). A decrease in Kir4.1 expression in SGCs was sufficient to evoke spontaneous pain in rats (Vit, Ohara, Bhargava, Kelley, & Jasmin, 2008), which most likely contributed to inflammation and nerve injury–evoked pain (Silva et al., 2017; Takeda, Takahashi, Nasu, & Matsumoto, 2011; Takeda, Tanimoto, Nasu, & Matsumoto, 2008; Vit et al., 2008). It is not clear how a reduction of Kir outward K+ currents in SGCs can increase the activity of the nociceptive neurons. Inhibition of Kir currents in glial cells in the hippocampus has been shown to increase extracellular K+ concentration, but the amplitude was low, and the mechanisms were not well described (D’Ambrosio, Gordon, & Winn, 2002). The depolarization of the plasma membrane consecutive to a diminution of Kir currents in SGCs could also increase the secretion of algogenic substances like the pro-inflammatory chemokines that would activate the neurons.

The role of Kir channels on peripheral and central pain mechanisms remains to be fully elucidated, but these channels already appear to be some of the important mediators of antinociceptive activity of GPCRs like opioids receptors. Of course, Kir channel openers could have antinociceptive activity, but one must also consider their implication in other diseases with the use of KATP channels openers as antihypertensive drug (i.e., pinacidil) or the use of sulfonylureas KATP channels inhibitors for the treatment of type 2 diabetes (i.e., glibenclamide) (Bhave et al., 2010). Clinical trials with KATP channel openers reported headache as a prevalent side effect in non-migraine sufferers (Al-Karagholi, Hansen, Severinsen, Jansen-Olesen, & Ashina, 2017). This supports a role for KATP in migraine (Ploug et al., 2012) and challenges the use of KATP channel activators for the treatment of pain.

Conclusion

The K+ channel family is one of the most complex families of ion channels. The diversity of this channel family is a real challenge for the study of pain. Certainly rapid progress is being made using single-cell sequencing of mRNA transcripts in sensory neurons, but functional studies are necessary to decipher the role of individual K+ channels in the fine-tuning of somatosensory perception and pain. The diminution of the expression of K+ channels is one of the most common observations in the studies of inflammatory and neuropathic pain. Nevertheless, as demonstrated in many studies, K+ channel enhancers could have a real therapeutic potential against the many facets of chronic pain. The diversity of the K+ channel family could therefore be a real opportunity for the development of innovative and specific therapeutic strategies adapted to different causes of pain resistant to current therapies.

References

Acosta, C., Djouhri, L., Watkins, R., Berry, C., Bromage, K., & Lawson, S. N. (2014). TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits spontaneous pain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 34(4), 1494–1509. doi:10.1523/JNEUROSCI.4528-13.2014Find this resource:

Al-Karagholi, M. A., Hansen, J. M., Severinsen, J., Jansen-Olesen, I., & Ashina, M. (2017). The KATP channel in migraine pathophysiology: A novel therapeutic target for migraine. The Journal of Headache and Pain, 18(1), 90. doi:10.1186/s10194-017-0800-8Find this resource:

Alloui, A., Zimmermann, K., Mamet, J., Duprat, F., Noel, J., Chemin, J., … Lazdunski, M. (2006). TREK-1, a K+ channel involved in polymodal pain perception. The EMBO Journal, 25(11), 2368–2376. doi:10.1038/sj.emboj.7601116Find this resource:

Alvarez-Leefmans, F. J., Gamino, S. M., Giraldez, F., & Nogueron, I. (1988). Intracellular chloride regulation in amphibian dorsal root ganglion neurones studied with ion-selective microelectrodes. The Journal of Physiology, 406, 225–246.Find this resource:

Alves, D. P., Tatsuo, M. A., Leite, R., & Duarte, I. D. (2004). Diclofenac-induced peripheral antinociception is associated with ATP-sensitive K+ channels activation. Life Sciences, 74(20), 2577–2591. doi:10.1016/j.lfs.2003.10.012Find this resource:

Andres-Enguix, I., Shang, L., Stansfeld, P. J., Morahan, J. M., Sansom, M. S., Lafreniere, R. G., … Tucker, S. J. (2012). Functional analysis of missense variants in the TRESK (KCNK18) K channel. Scientific Reports, 2, 237. doi:10.1038/srep00237Find this resource:

Ataga, K. I., Smith, W. R., De Castro, L. M., Swerdlow, P., Saunthararajah, Y., Castro, O., … Investigators, I. C. A. (2008). Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood, 111(8), 3991–3997. doi:10.1182/blood-2007-08-110098Find this resource:

Bahia, P. K., Suzuki, R., Benton, D. C., Jowett, A. J., Chen, M. X., Trezise, D. J., … Moss, G. W. (2005). A functional role for small-conductance calcium-activated potassium channels in sensory pathways including nociceptive processes. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 25(14), 3489–3498. doi:10.1523/JNEUROSCI.0597-05.2005Find this resource:

Baillie, L. D., Schmidhammer, H., & Mulligan, S. J. (2015). Peripheral mu-opioid receptor mediated inhibition of calcium signaling and action potential-evoked calcium fluorescent transients in primary afferent CGRP nociceptive terminals. Neuropharmacology, 93, 267–273. doi:10.1016/j.neuropharm.2015.02.011Find this resource:

Baumann, T. K., Chaudhary, P., & Martenson, M. E. (2004). Background potassium channel block and TRPV1 activation contribute to proton depolarization of sensory neurons from humans with neuropathic pain. European Journal of Neuroscience, 19(5), 1343-1351.Find this resource:

Bautista, D. M., Sigal, Y. M., Milstein, A. D., Garrison, J. L., Zorn, J. A., Tsuruda, P. R., … Julius, D. (2008). Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nature Neuroscience, 11(7), 772–779. doi:10.1038/nn.2143Find this resource:

Berkefeld, H., Fakler, B., & Schulte, U. (2010). Ca2+-activated K+ channels: From protein complexes to function. Physiological Reviews, 90(4), 1437–1459. doi:10.1152/physrev.00049.2009Find this resource:

Bhattacharjee, A., & Kaczmarek, L. K. (2005). For K+ channels, Na+ is the new Ca2+. Trends in Neurosciences, 28(8), 422–428. doi:10.1016/j.tins.2005.06.003Find this resource:

Bhave, G., Lonergan, D., Chauder, B. A., & Denton, J. S. (2010). Small-molecule modulators of inward rectifier K+ channels: Recent advances and future possibilities. Future in Medicinal Chemistry, 2(5), 757–774. doi:10.4155/fmc.10.179Find this resource:

Bocksteins, E. (2016). Kv5, Kv6, Kv8, and Kv9 subunits: No simple silent bystanders. The Journal of General Physiology, 147(2), 105–125. doi:10.1085/jgp.201511507Find this resource:

Bocksteins, E., Labro, A. J., Mayeur, E., Bruyns, T., Timmermans, J. P., Adriaensen, D., & Snyders, D. J. (2009). Conserved negative charges in the N-terminal tetramerization domain mediate efficient assembly of Kv2.1 and Kv2.1/Kv6.4 channels. The Journal of Biological Chemistry, 284(46), 31625–31634. doi:10.1074/jbc.M109.039479Find this resource:

Boettger, M. K., Till, S., Chen, M. X., Anand, U., Otto, W. R., Plumpton, C., … Anand, P. (2002). Calcium-activated potassium channel SK1- and IK1-like immunoreactivity in injured human sensory neurones and its regulation by neurotrophic factors. Brain, 125(Pt. 2), 252–263.Find this resource:

Bruehl, S., Denton, J. S., Lonergan, D., Koran, M. E., Chont, M., Sobey, C., … Thornton-Wells, T. A. (2013). Associations between KCNJ6 (GIRK2) gene polymorphisms and pain-related phenotypes. Pain, 154(12), 2853–2859. doi:10.1016/j.pain.2013.08.026Find this resource:

Burchiel, K. J., & Russell, L. C. (1985). Effects of potassium channel-blocking agents on spontaneous discharges from neuromas in rats. Journal of Neurosurgery, 63(2), 246–249. doi:10.3171/jns.1985.63.2.0246Find this resource:

Cai, J., Fang, D., Liu, X. D., Li, S., Ren, J., & Xing, G. G. (2015). Suppression of KCNQ/M (Kv7) potassium channels in the spinal cord contributes to the sensitization of dorsal horn WDR neurons and pain hypersensitivity in a rat model of bone cancer pain. Oncology Reports, 33(3), 1540–1550. doi:10.3892/or.2015.3718Find this resource:

Callejo, G., Giblin, J. P., & Gasull, X. (2013). Modulation of TRESK Background K(+) channel by membrane stretch. PloS One, 8(5), e64471. doi:10.1371/journal.pone.0064471Find this resource:

Calvo, M., Richards, N., Schmid, A. B., Barroso, A., Zhu, L., Ivulic, D., … Bennett, D. L. (2016). Altered potassium channel distribution and composition in myelinated axons suppresses hyperexcitability following injury. Elife, 5, e12661. doi:10.7554/eLife.12661Find this resource:

Cao, X. H., Byun, H. S., Chen, S. R., Cai, Y. Q., & Pan, H. L. (2010). Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: Role of brain-derived neurotrophic factor. Journal of Neurochemistry, 114(5), 1460–1475. doi:10.1111/j.1471-4159.2010.06863.xFind this resource:

Cao, X. H., Chen, S. R., Li, L., & Pan, H. L. (2012). Nerve injury increases brain-derived neurotrophic factor levels to suppress BK channel activity in primary sensory neurons. Journal of Neurochemistry, 121(6), 944–953. doi:10.1111/j.1471-4159.2012.07736.xFind this resource:

Castellanos, A., Andres, A., Bernal, L., Callejo, G., Comes, N., Gual, A., … Gasull, X. (2018). Pyrethroids inhibit K2P channels and activate sensory neurons: Basis of insecticide-induced paraesthesias. Pain, 159(1), 92–105. doi:10.1097/j.pain.0000000000001068Find this resource:

Chen, S. R., Cai, Y. Q., & Pan, H. L. (2009). Plasticity and emerging role of BKCa channels in nociceptive control in neuropathic pain. Journal of Neurochemistry, 110(1), 352–362. doi:10.1111/j.1471-4159.2009.06138.xFind this resource:

Chi, X. X., Jiang, X., & Nicol, G. D. (2007). ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons. Brain Research, 1145, 28–40. doi:10.1016/j.brainres.2007.01.103Find this resource:

Chien, L. Y., Cheng, J. K., Chu, D., Cheng, C. F., & Tsaur, M. L. (2007). Reduced expression of A-type potassium channels in primary sensory neurons induces mechanical hypersensitivity. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 27(37), 9855–9865. doi:10.1523/JNEUROSCI.0604-07.2007Find this resource:

Chiu, I. M., Barrett, L. B., Williams, E. K., Strochlic, D. E., Lee, S., Weyer, A. D., … Woolf, C. J. (2014). Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity. Elife Dec 19, 3.Find this resource:

Chung, M. K., Cho, Y. S., Bae, Y. C., Lee, J., Zhang, X., & Ro, J. Y. (2014). Peripheral G protein-coupled inwardly rectifying potassium channels are involved in delta-opioid receptor-mediated anti-hyperalgesia in rat masseter muscle. European Journal of Pain (London, England), 18(1), 29–38. doi:10.1002/j.1532-2149.2013.00343.xFind this resource:

Cisneros, E., Roza, C., Jackson, N., & Lopez-Garcia, J. A. (2015). A new regulatory mechanism for Kv7.2 protein during neuropathy: Enhanced transport from the soma to axonal terminals of injured sensory neurons. Frontiers in Cellular Neuroscience, 9, 470. doi:10.3389/fncel.2015.00470Find this resource:

Coetzee, W. A., Amarillo, Y., Chiu, J., Chow, A., Lau, D., McCormack, T., … Rudy, B. (1999). Molecular diversity of K+ channels. Annals of the New York Academy of Sciences 868, 233–285.Find this resource:

Conner, L. B., Alvarez, P., Bogen, O., & Levine, J. D. (2016). Role of Kv4.3 in vibration-induced muscle pain in the rat. The Journal of Pain: Official Journal of the American Pain Society, 17(4), 444–450. doi:10.1016/j.jpain.2015.12.007Find this resource:

Costigan, M., Belfer, I., Griffin, R. S., Dai, F., Barrett, L. B., Coppola, G., … Woolf, C. J. (2010). Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain, 133(9), 2519–2527. doi:10.1093/brain/awq195Find this resource:

Cruz, H. G., Berton, F., Sollini, M., Blanchet, C., Pravetoni, M., Wickman, K., & Luscher, C. (2008). Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(15), 4069–4077. doi:10.1523/JNEUROSCI.0267-08.2008Find this resource:

D’Ambrosio, R., Gordon, D. S., & Winn, H. R. (2002). Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus. The Journal of Neurophysiology, 87(1), 87–102. doi:10.1152/jn.00240.2001Find this resource:

Delmas, P., Hao, J., & Rodat-Despoix, L. (2011). Molecular mechanisms of mechanotransduction in mammalian sensory neurons. Nature Reviews. Neuroscience, 12(3), 139–153. doi:10.1038/nrn2993Find this resource:

Descoeur, J., Pereira, V., Pizzoccaro, A., Francois, A., Ling, B., Maffre, V., … Bourinet, E. (2011). Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Molecular Medicine, 3(5), 266–278. doi:10.1002/emmm.201100134Find this resource:

Devaux, J. J., Kleopa, K. A., Cooper, E. C., & Scherer, S. S. (2004). KCNQ2 is a nodal K+ channel. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 24(5), 1236–1244. doi:10.1523/JNEUROSCI.4512-03.2004Find this resource:

Devilliers, M., Busserolles, J., Lolignier, S., Deval, E., Pereira, V., Alloui, A., … Eschalier, A. (2013). Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nature Communications, 4, 2941. doi:10.1038/ncomms3941Find this resource:

Dobler, T., Springauf, A., Tovornik, S., Weber, M., Schmitt, A., Sedlmeier, R., … Doring, F. (2007). TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. The Journal of Physiology, 585(Pt. 3), 867–879. doi:10.1113/jphysiol.2007.145649Find this resource:

Dolga, A. M., Netter, M. F., Perocchi, F., Doti, N., Meissner, L., Tobaben, S., … Culmsee, C. (2013). Mitochondrial small conductance SK2 channels prevent glutamate-induced oxytosis and mitochondrial dysfunction. The Journal of Biological Chemistry, 288(15), 10792–10804. doi:10.1074/jbc.M113.453522Find this resource:

Du, X., Gao, H., Jaffe, D., Zhang, H., & Gamper, N. (2018). M-type K(+) channels in peripheral nociceptive pathways. British Journal of Pharmacology, 175(12), 2158–2172. doi:10.1111/bph.13978Find this resource:

Duan, K. Z., Xu, Q., Zhang, X. M., Zhao, Z. Q., Mei, Y. A., & Zhang, Y. Q. (2012). Targeting A-type K(+) channels in primary sensory neurons for bone cancer pain in a rat model. Pain, 153(3), 562–574. doi:10.1016/j.pain.2011.11.020Find this resource:

Enyedi, P., & Czirjak, G. (2010). Molecular background of leak K+ currents: Two-pore domain potassium channels. Physiological Reviews, 90(2), 559–605. doi:10.1152/physrev.00029.2009Find this resource:

Fang, X., McMullan, S., Lawson, S. N., & Djouhri, L. (2005). Electrophysiological differences between nociceptive and non-nociceptive dorsal root ganglion neurones in the rat in vivo. The Journal of Physiology, 565(Pt. 3), 927–943. doi:10.1113/jphysiol.2005.086199Find this resource:

Fay, A. J., Qian, X., Jan, Y. N., & Jan, L. Y. (2006). SK channels mediate NADPH oxidase-independent reactive oxygen species production and apoptosis in granulocytes. Proceedings of the National Academy of Sciences of the United States of America, 103(46), 17548–17553. doi:10.1073/pnas.0607914103Find this resource:

Feinshreiber, L., Singer-Lahat, D., Friedrich, R., Matti, U., Sheinin, A., Yizhar, O., … Lotan, I. (2010). Non-conducting function of the Kv2.1 channel enables it to recruit vesicles for release in neuroendocrine and nerve cells. Journal of Cell Science, 123(Pt. 11), 1940–1947. doi:10.1242/jcs.063719Find this resource:

Fink, M., Duprat, F., Lesage, F., Reyes, R., Romey, G., Heurteaux, C., & Lazdunski, M. (1996). Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. The EMBO Journal, 15(24), 6854–6862.Find this resource:

Flegel, C., Schobel, N., Altmuller, J., Becker, C., Tannapfel, A., Hatt, H., & Gisselmann, G. (2015). RNA-Seq analysis of human trigeminal and dorsal root ganglia with a focus on chemoreceptors. PloS One, 10(6), e0128951. doi:10.1371/journal.pone.0128951Find this resource:

Gao, X. F., Zhang, H. L., You, Z. D., Lu, C. L., & He, C. (2007). G protein-coupled inwardly rectifying potassium channels in dorsal root ganglion neurons. Acta Pharmacological Sinica, 28(2), 185–190. doi:10.1111/j.1745-7254.2007.00478.xFind this resource:

Giblin, J. P., Etayo, I., Castellanos, A., Andres-Bilbe, A., & Gasull, X. (2019). Anionic phospholipids bind to and modulate the activity of human TRESK background K(+) Channel. Molecular Neurobiology, 56(4), 2524–2541. doi:10.1007/s12035-018-1244-0Find this resource:

Gold, M. S., Shuster, M. J., & Levine, J. D. (1996). Characterization of six voltage-gated K+ currents in adult rat sensory neurons. The Journal of Neurophysiology, 75(6), 2629–2646.Find this resource:

Grabauskas, G., Heldsinger, A., Wu, X., Xu, D., Zhou, S., & Owyang, C. (2011). Diabetic visceral hypersensitivity is associated with activation of mitogen-activated kinase in rat dorsal root ganglia. Diabetes, 60(6), 1743–1751. doi:10.2337/db10-1507Find this resource:

Gueguinou, M., Chantome, A., Fromont, G., Bougnoux, P., Vandier, C., & Potier-Cartereau, M. (2014). KCa and Ca(2+) channels: The complex thought. Biochimica et Biophysica Acta, 1843(10), 2322–2333. doi:10.1016/j.bbamcr.2014.02.019Find this resource:

Guo, Z., & Cao, Y. Q. (2014). Over-expression of TRESK K(+) channels reduces the excitability of trigeminal ganglion nociceptors. PloS One, 9(1), e87029. doi:10.1371/journal.pone.0087029Find this resource:

Guo, Z., Liu, P., Ren, F., & Cao, Y. Q. (2014). Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons. The Journal of Neurophysiology, 112(3), 568–579. doi:10.1152/jn.00267.2014Find this resource:

Gutierrez, V. P., Zambelli, V. O., Picolo, G., Chacur, M., Sampaio, S. C., Brigatte, P., … Cury, Y. (2012). The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K(+) channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats. Behavioural Pharmacology, 23(1), 14–24. doi:10.1097/FBP.0b013e32834eafbcFind this resource:

Gutman, G. A., Chandy, K. G., Grissmer, S., Lazdunski, M., McKinnon, D., Pardo, L. A., … Wang, X. (2005). International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacological Reviews, 57(4), 473–508. doi:10.1124/pr.57.4.10Find this resource:

Hao, J., Padilla, F., Dandonneau, M., Lavebratt, C., Lesage, F., Noel, J., & Delmas, P. (2013). Kv1.1 channels act as mechanical brake in the senses of touch and pain. Neuron, 77(5), 899–914. doi:10.1016/j.neuron.2012.12.035Find this resource:

Häring, M., Zeisel, A., Hochgerner, H., Rinwa, P., Jakobsson, J. E. T., Lonnerberg, P., … Ernfors, P. (2018). Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types. Nature Neuroscience, 21(6), 869–880. doi:10.1038/s41593-018-0141-1Find this resource:

Heidenreich, M., Lechner, S. G., Vardanyan, V., Wetzel, C., Cremers, C. W., De Leenheer, E. M., … Lewin, G. R. (2011). KCNQ4 K(+) channels tune mechanoreceptors for normal touch sensation in mouse and man. Nature Neuroscience, 15(1), 138–145. doi:10.1038/nn.2985Find this resource:

Hibino, H., Inanobe, A., Furutani, K., Murakami, S., Findlay, I., & Kurachi, Y. (2010). Inwardly rectifying potassium channels: Their structure, function, and physiological roles. Physiological Reviews, 90(1), 291–366. doi:10.1152/physrev.00021.2009Find this resource:

Hogan, Q., Lirk, P., Poroli, M., Rigaud, M., Fuchs, A., Fillip, P., … Sapunar, D. (2008). Restoration of calcium influx corrects membrane hyperexcitability in injured rat dorsal root ganglion neurons. Anesthesia and Analgesia, 107(3), 1045–1051. doi:10.1213/ane.0b013e31817bd1f0Find this resource:

Honma, Y., Yamakage, M., & Ninomiya, T. (1999). Effects of adrenergic stimulus on the activities of Ca2+ and K+ channels of dorsal root ganglion neurons in a neuropathic pain model. Brain Research, 832(1–2), 195–206.Find this resource:

Honore, E., Maingret, F., Lazdunski, M., & Patel, A. J. (2002). An intracellular proton sensor commands lipid- and mechano-gating of the K(+) channel TREK-1. The EMBO Journal, 21(12), 2968–2976. doi:10.1093/emboj/cdf288Find this resource:

Huang, F., Wang, X., Ostertag, E. M., Nuwal, T., Huang, B., Jan, Y. N., … Jan, L. Y. (2013). TMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processing. Nature Neuroscience, 16(9), 1284–1290. doi:10.1038/nn.3468Find this resource:

Ikeda, K., Kobayashi, T., Kumanishi, T., Niki, H., & Yano, R. (2000). Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia. Neuroscience Research, 38(1), 113–116. doi:10.1016/s0168-0102(00)00144-9Find this resource:

Ishikawa, K., Tanaka, M., Black, J. A., & Waxman, S. G. (1999). Changes in expression of voltage-gated potassium channels in dorsal root ganglion neurons following axotomy. Muscle & Nerve, 22(4), 502–507.Find this resource:

Kaczmarek, L. K., Aldrich, R. W., Chandy, K. G., Grissmer, S., Wei, A. D., & Wulff, H. (2017). International Union of Basic and Clinical Pharmacology. C. Nomenclature and properties of calcium-activated and sodium-activated potassium channels. Pharmacological Reviews, 69(1), 1–11. doi:10.1124/pr.116.012864Find this resource:

Kang, D., Choe, C., & Kim, D. (2005). Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. The Journal of Physiology, 564(Pt. 1), 103–116. doi:10.1113/jphysiol.2004.081059Find this resource:

Kang, D., & Kim, D. (2006). TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. American Journal of Physiology. Cell Physiology, 291(1), C138–C146. doi:10.1152/ajpcell.00629.2005Find this resource:

Kang, D., Kim, G. T., Kim, E. J., La, J. H., Lee, J. S., Lee, E. S., … Han, J. (2008). Lamotrigine inhibits TRESK regulated by G-protein coupled receptor agonists. Biochemical and Biophysical Research Communications, 367(3), 609–615. doi:10.1016/j.bbrc.2008.01.008Find this resource:

Kawabata, A., Kawao, N., Hironaka, Y., Ishiki, T., Matsunami, M., & Sekiguchi, F. (2006). Antiallodynic effect of etidronate, a bisphosphonate, in rats with adjuvant-induced arthritis: Involvement of ATP-sensitive K+ channels. Neuropharmacology, 51(2), 182–190. doi:10.1016/j.neuropharm.2006.03.015Find this resource:

Kawano, T., Zoga, V., Gemes, G., McCallum, J. B., Wu, H. E., Pravdic, D., … Sarantopoulos, C. (2009). Suppressed Ca2+/CaM/CaMKII-dependent K(ATP) channel activity in primary afferent neurons mediates hyperalgesia after axotomy. Proceedings of the National Academy of Sciences of the United States of America, 106(21), 8725–8730. doi:10.1073/pnas.0901815106Find this resource:

Kawano, T., Zoga, V., McCallum, J. B., Wu, H. E., Gemes, G., Liang, M. Y., … Sarantopoulos, C. D. (2009). ATP-sensitive potassium currents in rat primary afferent neurons: Biophysical, pharmacological properties, and alterations by painful nerve injury. Neuroscience, 162(2), 431–443. doi:10.1016/j.neuroscience.2009.04.076Find this resource:

Keen, J. E., Khawaled, R., Farrens, D. L., Neelands, T., Rivard, A., Bond, C. T., … Maylie, J. (1999). Domains responsible for constitutive and Ca(2+)-dependent interactions between calmodulin and small conductance Ca(2+)-activated potassium channels. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 19(20), 8830–8838.Find this resource:

Kim, D. S., Choi, J. O., Rim, H. D., & Cho, H. J. (2002). Downregulation of voltage-gated potassium channel alpha gene expression in dorsal root ganglia following chronic constriction injury of the rat sciatic nerve. Brain Research. Molecular Brain Research, 105(1–2), 146–152.Find this resource:

King, C. H., Lancaster, E., Salomon, D., Peles, E., & Scherer, S. S. (2014). Kv7.2 regulates the function of peripheral sensory neurons. The Journal of Comparative Neurology, 522(14), 3262–3280. doi:10.1002/cne.23595Find this resource:

King, C. H., & Scherer, S. S. (2012). Kv7.5 is the primary Kv7 subunit expressed in C-fibers. The Journal of Comparative Neurology, 520(9), 1940–1950. doi:10.1002/cne.23019Find this resource:

Kirchhoff, C., Leah, J. D., Jung, S., & Reeh, P. W. (1992). Excitation of cutaneous sensory nerve endings in the rat by 4-aminopyridine and tetraethylammonium. The Journal of Neurophysiology, 67(1), 125–131.Find this resource:

Kollert, S., Dombert, B., Doring, F., & Wischmeyer, E. (2015). Activation of TRESK channels by the inflammatory mediator lysophosphatidic acid balances nociceptive signalling. Scientific Reports, 5, 12548. doi:10.1038/srep12548Find this resource:

Kubo, Y., Adelman, J. P., Clapham, D. E., Jan, L. Y., Karschin, A., Kurachi, Y., … Vandenberg, C. A. (2005). International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacological Reviews, 57(4), 509–526. doi:10.1124/pr.57.4.11Find this resource:

Kummer, K. K., Kalpachidou, T., Kress, M., & Langeslag, M. (2018). Signatures of altered gene expression in dorsal root ganglia of a Fabry disease mouse model. Frontiers in Molecular Neuroscience, 10, 449. doi:10.3389/fnmol.2017.00449Find this resource:

Kurachi, Y., Nakajima, T., & Sugimoto, T. (1987). Quinidine inhibition of the muscarine receptor-activated K+ channel current in atrial cells of guinea pig. Naunyn-Schmiedeberg’s Archives of Pharmacology, 335(2), 216–218.Find this resource:

La, J. H., & Gebhart, G. F. (2011). Colitis decreases mechanosensitive K2P channel expression and function in mouse colon sensory neurons. American Journal of Physiology. Gastrointestinal and Liver Physiology, 301(1), G165–G174. doi:10.1152/ajpgi.00417.2010Find this resource:

Lafreniere, R. G., Cader, M. Z., Poulin, J. F., Andres-Enguix, I., Simoneau, M., Gupta, N., … Rouleau, G. A. (2010). A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nature Medicine, 16(10), 1157–1160. doi:10.1038/nm.2216Find this resource:

Lang, P. M., Fleckenstein, J., Passmore, G. M., Brown, D. A., & Grafe, P. (2008). Retigabine reduces the excitability of unmyelinated peripheral human axons. Neuropharmacology, 54(8), 1271–1278. doi:10.1016/j.neuropharm.2008.04.006Find this resource:

LaPaglia, D. M., Sapio, M. R., Burbelo, P. D., Thierry-Mieg, J., Thierry-Mieg, D., Raithel, S. J., … Mannes, A. J. (2017). RNA-Seq investigations of human post-mortem trigeminal ganglia. Cephalalgia, 38(5), 912–932. doi:10.1177/0333102417720216Find this resource:

Laumet, G., Garriga, J., Chen, S. R., Zhang, Y., Li, D. P., Smith, T. M., … Pan, H. L. (2015). G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition. Nature Neuroscience, 18(12), 1746–1755. doi:10.1038/nn.4165Find this resource:

Lesage, F., Maingret, F., & Lazdunski, M. (2000). Cloning and expression of human TRAAK, a polyunsaturated fatty acids-activated and mechano-sensitive K(+) channel. FEBS Letters, 471(2–3), 137–140. doi:10.1016/S0014-5793(00)01388-0Find this resource:

Li, W., Gao, S. B., Lv, C. X., Wu, Y., Guo, Z. H., Ding, J. P., & Xu, T. (2007). Characterization of voltage-and Ca2+-activated K+ channels in rat dorsal root ganglion neurons. Journal of Cellular Physiology, 212(2), 348–357. doi:10.1002/jcp.21007Find this resource:

Li, B. Y., Glazebrook, P., Kunze, D. L., & Schild, J. H. (2011). KCa1.1 channel contributes to cell excitability in unmyelinated but not myelinated rat vagal afferents. American Journal of Physiology-Cell Physiology, 300(6), C1393-1403. doi:10.1152/ajpcell.00278.2010Find this resource:

Li, Z., Gu, X., Sun, L., Wu, S., Liang, L., Cao, J., … Tao, Y. X. (2015). Dorsal root ganglion myeloid zinc finger protein 1 contributes to neuropathic pain after peripheral nerve trauma. Pain, 156(4), 711–721. doi:10.1097/j.pain.0000000000000103Find this resource:

Liang, L., Gu, X., Zhao, J. Y., Wu, S., Miao, X., Xiao, J., … Tao, Y. X. (2016). G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons. Scientific Reports, 6, 37704. doi:10.1038/srep37704Find this resource:

Ling, J., Erol, F., & Gu, J. G. (2018). Role of KCNQ2 channels in orofacial cold sensitivity: KCNQ2 upregulation in trigeminal ganglion neurons after infraorbital nerve chronic constrictive injury. Neuroscience Letters, 664, 84–90. doi:10.1016/j.neulet.2017.11.026Find this resource:

Ling, J., Erol, F., Viatchenko-Karpinski, V., Kanda, H., & Gu, J. G. (2017). Orofacial neuropathic pain induced by oxaliplatin: Downregulation of KCNQ2 channels in V2 trigeminal ganglion neurons and treatment by the KCNQ2 channel potentiator retigabine. Molecular Pain, 13, 1744806917724715. doi:10.1177/1744806917724715Find this resource:

Linley, J. E., Ooi, L., Pettinger, L., Kirton, H., Boyle, J. P., Peers, C., & Gamper, N. (2012). Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons. Proceedings of the National Academy of Sciences of the United States of America, 109(24), E1578–E1586. doi:10.1073/pnas.1201544109Find this resource:

Linley, J. E., Pettinger, L., Huang, D., & Gamper, N. (2012). M channel enhancers and physiological M channel block. The Journal of Physiology, 590(4), 793–807. doi:10.1113/jphysiol.2011.223404Find this resource:

Liu, B., Linley, J. E., Du, X., Zhang, X., Ooi, L., Zhang, H., & Gamper, N. (2010). The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl- channels. The Journal of Clinical Investigation, 120(4), 1240–1252. doi:10.1172/JCI41084Find this resource:

Liu, P., Xiao, Z., Ren, F., Guo, Z., Chen, Z., Zhao, H., & Cao, Y. Q. (2013). Functional analysis of a migraine-associated TRESK K+ channel mutation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33(31), 12810–12824. doi:10.1523/JNEUROSCI.1237-13.2013Find this resource:

Lu, R., Bausch, A. E., Kallenborn-Gerhardt, W., Stoetzer, C., Debruin, N., Ruth, P., … Schmidtko, A. (2015). Slack channels expressed in sensory neurons control neuropathic pain in mice. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 35(3), 1125–1135. doi:10.1523/JNEUROSCI.2423-14.2015Find this resource:

Lu, R., Flauaus, C., Kennel, L., Petersen, J., Drees, O., Kallenborn-Gerhardt, W., … Schmidtko, A. (2017). KCa3.1 channels modulate the processing of noxious chemical stimuli in mice. Neuropharmacology, 125, 386–395. doi:10.1016/j.neuropharm.2017.08.021Find this resource:

Lu, R., Lukowski, R., Sausbier, M., Zhang, D. D., Sisignano, M., Schuh, C. D., … Schmidtko, A. (2014). BKCa channels expressed in sensory neurons modulate inflammatory pain in mice. Pain, 155(3), 556–565. doi:10.1016/j.pain.2013.12.005Find this resource:

Lyu, C., Mulder, J., Barde, S., Sahlholm, K., Zeberg, H., Nilsson, J., … Shi, T. J. (2015). G protein-gated inwardly rectifying potassium channel subunits 1 and 2 are down-regulated in rat dorsal root ganglion neurons and spinal cord after peripheral axotomy. Molecular Pain, 11, 44. doi:10.1186/s12990-015-0044-zFind this resource:

Ma, C., Rosenzweig, J., Zhang, P., Johns, D. C., & LaMotte, R. H. (2010). Expression of inwardly rectifying potassium channels by an inducible adenoviral vector reduced the neuronal hyperexcitability and hyperalgesia produced by chronic compression of the spinal ganglion. Molecular Pain, 6, 65. doi:10.1186/1744-8069-6-65Find this resource:

Madrid, R., de la Pena, E., Donovan-Rodriguez, T., Belmonte, C., & Viana, F. (2009). Variable threshold of trigeminal cold-thermosensitive neurons is determined by a balance between TRPM8 and Kv1 potassium channels. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 29(10), 3120–3131. doi:10.1523/JNEUROSCI.4778-08.2009Find this resource:

Maingret, F., Lauritzen, I., Patel, A. J., Heurteaux, C., Reyes, R., Lesage, F., … Honore, E. (2000). TREK-1 is a heat-activated background K(+) channel. The EMBO Journal, 19(11), 2483–2491. doi:10.1093/emboj/19.11.2483Find this resource:

Maingret, F., Patel, A. J., Lesage, F., Lazdunski, M., & Honore, E. (2000). Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. The Journal of Biological Chemistry, 275(14), 10128–10133.Find this resource:

Manteniotis, S., Lehmann, R., Flegel, C., Vogel, F., Hofreuter, A., Schreiner, B. S., … Gisselmann, G. (2013). Comprehensive RNA-Seq expression analysis of sensory ganglia with a focus on ion channels and GPCRs in Trigeminal ganglia. PloS One, 8(11), e79523. doi:10.1371/journal.pone.0079523Find this resource:

Mao, Q., Yuan, J., Ming, X., Wu, S., Chen, L., Bekker, A., … Tao, Y. X. (2017). Role of dorsal root ganglion K2p1.1 in peripheral nerve injury-induced neuropathic pain. Molecular Pain, 13, 1744806917701135. doi:10.1177/1744806917701135Find this resource:

Marker, C. L., Lujan, R., Loh, H. H., & Wickman, K. (2005). Spinal G-protein-gated potassium channels contribute in a dose-dependent manner to the analgesic effect of mu- and delta- but not kappa-opioids. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 25(14), 3551–3559. doi:10.1523/JNEUROSCI.4899-04.2005Find this resource:

Marker, C. L., Stoffel, M., & Wickman, K. (2004). Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 24(11), 2806–2812. doi:10.1523/JNEUROSCI.5251-03.200424/11/2806Find this resource:

Marsh, B., Acosta, C., Djouhri, L., & Lawson, S. N. (2012). Leak K(+) channel mRNAs in dorsal root ganglia: relation to inflammation and spontaneous pain behaviour. Molecular and Cellular Neurosciences, 49(3), 375–386. doi:10.1016/j.mcn.2012.01.002Find this resource:

Martinez-Espinosa, P. L., Wu, J., Yang, C., Gonzalez-Perez, V., Zhou, H., Liang, H., … Lingle, C. J. (2015). Knockout of Slo2.2 enhances itch, abolishes KNa current, and increases action potential firing frequency in DRG neurons. Elife, 4. pii: e10013. doi:10.7554/eLife.10013Find this resource:

Matsuyoshi, H., Takimoto, K., Yunoki, T., Erickson, V. L., Tyagi, P., Hirao, Y., … Yoshimura, N. (2012). Distinct cellular distributions of Kv4 pore-forming and auxiliary subunits in rat dorsal root ganglion neurons. Life Sciences, 91(7–8), 258–263. doi:10.1016/j.lfs.2012.07.007Find this resource:

Medhurst, A. D., Rennie, G., Chapman, C. G., Meadows, H., Duckworth, M. D., Kelsell, R. E., … Pangalos, M. N. (2001). Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Brain Research. Molecular Brain Research, 86(1–2), 101–114. doi:10.1016/s0169-328x(00)00263-1Find this resource:

Mo, K., Wu, S., Gu, X., Xiong, M., Cai, W., Atianjoh, F. E., … Tao, Y. X. (2018). MBD1 contributes to the genesis of acute pain and neuropathic pain by epigenetic silencing of Oprm1 and Kcna2 genes in primary sensory neurons. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 38(46), 9883–9899. doi:10.1523/JNEUROSCI.0880-18.2018Find this resource:

Mongan, L. C., Hill, M. J., Chen, M. X., Tate, S. N., Collins, S. D., Buckby, L., & Grubb, B. D. (2005). The distribution of small and intermediate conductance calcium-activated potassium channels in the rat sensory nervous system. Neuroscience, 131(1), 161–175. doi:10.1016/j.neuroscience.2004.09.062Find this resource:

Morenilla-Palao, C., Luis, E., Fernandez-Pena, C., Quintero, E., Weaver, J. L., Bayliss, D. A., & Viana, F. (2014). Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell Reports, 8(5), 1571–1582. doi:10.1016/j.celrep.2014.08.003Find this resource:

Murata, Y., Yasaka, T., Takano, M., & Ishihara, K. (2016). Neuronal and glial expression of inward rectifier potassium channel subunits Kir2.x in rat dorsal root ganglion and spinal cord. Neuroscience Letters, 617, 59–65. doi:10.1016/j.neulet.2016.02.007Find this resource:

Nishizawa, D., Fukuda, K., Kasai, S., Ogai, Y., Hasegawa, J., Sato, N., … Ikeda, K. (2014). Association between KCNJ6 (GIRK2) gene polymorphism rs2835859 and post-operative analgesia, pain sensitivity, and nicotine dependence. Journal of Pharmacological Sciences, 126(3), 253–263.Find this resource:

Nishizawa, D., Nagashima, M., Katoh, R., Satoh, Y., Tagami, M., Kasai, S., … Ikeda, K. (2009). Association between KCNJ6 (GIRK2) gene polymorphisms and postoperative analgesic requirements after major abdominal surgery. PloS One, 4(9), e7060. doi:10.1371/journal.pone.0007060Find this resource:

Niu, K., Saloman, J. L., Zhang, Y., & Ro, J. Y. (2011). Sex differences in the contribution of ATP-sensitive K+ channels in trigeminal ganglia under an acute muscle pain condition. Neuroscience, 180, 344–352. doi:10.1016/j.neuroscience.2011.01.045Find this resource:

Nockemann, D., Rouault, M., Labuz, D., Hublitz, P., McKnelly, K., Reis, F. C., … Heppenstall, P. A. (2013). The K(+) channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Molecular Medicine, 5(8), 1263–1277. doi:10.1002/emmm.201201980Find this resource:

Noel, J., Sandoz, G., & Lesage, F. (2011). Molecular regulations governing TREK and TRAAK channel functions. Channels (Austin), 5(5), 402–409. doi:10.4161/chan.5.5.16469Find this resource:

Noel, J., Zimmermann, K., Busserolles, J., Deval, E., Alloui, A., Diochot, S., … Lazdunski, M. (2009). The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. The EMBO Journal, 28(9), 1308–1318. doi:10.1038/emboj.2009.57Find this resource:

Nuwer, M. O., Picchione, K. E., & Bhattacharjee, A. (2010). PKA-induced internalization of slack KNa channels produces dorsal root ganglion neuron hyperexcitability. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30(42), 14165–14172. doi:10.1523/JNEUROSCI.3150-10.2010Find this resource:

Ocana, M., & Baeyens, J. M. (1993). Differential effects of K+ channel blockers on antinociception induced by alpha 2-adrenoceptor, GABAB and kappa-opioid receptor agonists. British Journal of Pharmacology, 110(3), 1049–1054.Find this resource:

Ocana, M., Cendan, C. M., Cobos, E. J., Entrena, J. M., & Baeyens, J. M. (2004). Potassium channels and pain: Present realities and future opportunities. European Journal of Pharmacology, 500(1–3), 203–219. doi:10.1016/j.ejphar.2004.07.026Find this resource:

Ocana, M., Del Pozo, E., & Baeyens, J. M. (1993). Gliquidone, an ATP-dependent K+ channel antagonist, antagonizes morphine-induced hypermotility. European Journal of Pharmacology, 239(1–3), 253–255.Find this resource:

Ortiz, M. I., Castaneda-Hernandez, G., Izquierdo-Vega, J. A., Sanchez-Gutierrez, M., Ponce-Monter, H. A., & Granados-Soto, V. (2012). Role of ATP-sensitive K+ channels in the antinociception induced by non-steroidal anti-inflammatory drugs in streptozotocin-diabetic and non-diabetic rats. Pharmacology, Biochemistry, and Behavior, 102(1), 163–169. doi:10.1016/j.pbb.2012.03.032Find this resource:

Pagadala, P., Park, C. K., Bang, S., Xu, Z. Z., Xie, R. G., Liu, T., … Ji, R. R. (2013). Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: Involvement of Ca(2+)-activated small conductance potassium channels. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 33(33), 13425–13430. doi:10.1523/JNEUROSCI.0454-13.2013Find this resource:

Park, S. Y., Choi, J. Y., Kim, R. U., Lee, Y. S., Cho, H. J., & Kim, D. S. (2003). Downregulation of voltage-gated potassium channel alpha gene expression by axotomy and neurotrophins in rat dorsal root ganglia. Molecules and Cells, 16(2), 256–259.Find this resource:

Passmore, G. M., Reilly, J. M., Thakur, M., Keasberry, V. N., Marsh, S. J., Dickenson, A. H., & Brown, D. A. (2012). Functional significance of M-type potassium channels in nociceptive cutaneous sensory endings. Frontiers in Molecular Neuroscience, 5, 63. doi:10.3389/fnmol.2012.00063Find this resource:

Passmore, G. M., Selyanko, A. A., Mistry, M., Al-Qatari, M., Marsh, S. J., Matthews, E. A., … Brown, D. A. (2003). KCNQ/M currents in sensory neurons: Significance for pain therapy. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(18), 7227–7236.Find this resource:

Patel, A. J., Honore, E., Maingret, F., Lesage, F., Fink, M., Duprat, F., & Lazdunski, M. (1998). A mammalian two pore domain mechano-gated S-like K+ channel. The EMBO Journal, 17(15), 4283–4290. doi:10.1093/emboj/17.15.4283Find this resource:

Peiris, M., Hockley, J. R., Reed, D. E., Smith, E. S. J., Bulmer, D. C., & Blackshaw, L. A. (2017). Peripheral KV7 channels regulate visceral sensory function in mouse and human colon. Molecular Pain, 13, 1744806917709371. doi:10.1177/1744806917709371Find this resource:

Pereira, V., Busserolles, J., Christin, M., Devilliers, M., Poupon, L., Legha, W., … Noel, J. (2014). Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception. Pain, 155(12), 2534–2544. doi:10.1016/j.pain.2014.09.013S0304-3959(14)00436-9Find this resource:

Petersen, O. H., & Maruyama, Y. (1984). Calcium-activated potassium channels and their role in secretion. Nature, 307(5953), 693–696.Find this resource:

Phuket, T. R., & Covarrubias, M. (2009). Kv4 channels underlie the subthreshold-operating A-type K-current in nociceptive dorsal root ganglion neurons. Frontiers in Molecular Neuroscience, 2, 3. doi:10.3389/neuro.02.003.2009Find this resource:

Ploug, K. B., Amrutkar, D. V., Baun, M., Ramachandran, R., Iversen, A., Lund, T. M., … Jansen-Olesen, I. (2012). K(ATP) channel openers in the trigeminovascular system. Cephalalgia, 32(1), 55–65. doi:10.1177/0333102411430266Find this resource:

Pollema-Mays, S. L., Centeno, M. V., Ashford, C. J., Apkarian, A. V., & Martina, M. (2013). Expression of background potassium channels in rat DRG is cell-specific and down-regulated in a neuropathic pain model. Molecular and Cellular Neurosciences, 57, 1–9.Find this resource:

Pongs, O., & Schwarz, J. R. (2010). Ancillary subunits associated with voltage-dependent K+ channels. Physiological Reviews, 90(2), 755–796. doi:10.1152/physrev.00020.2009Find this resource:

Poupon, L., Lamoine, S., Pereira, V., Barriere, D. A., Lolignier, S., Giraudet, F., … Busserolles, J. (2018). Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin. Neuropharmacology, 140, 43–61. doi:10.1016/j.neuropharm.2018.07.026Find this resource:

Qian, A. H., Liu, X. Q., Yao, W. Y., Wang, H. Y., Sun, J., Zhou, L., & Yuan, Y. Z. (2009). Voltage-gated potassium channels in IB4-positive colonic sensory neurons mediate visceral hypersensitivity in the rat. The American Journal of Gastroenterology, 104(8), 2014–2027. doi:10.1038/ajg.2009.227Find this resource:

Qian, L. P., Shen, S. R., Chen, J. J., Ji, L. L., & Cao, S. (2016). Peripheral KATP activation inhibits pain sensitization induced by skin/muscle incision and retraction via the nuclear factor-kappaB/c-Jun N-terminal kinase signaling pathway. Molecular Medicine Reports, 14(3), 2632–2638. doi:10.3892/mmr.2016.5546Find this resource:

Rasband, M. N., Park, E. W., Vanderah, T. W., Lai, J., Porreca, F., & Trimmer, J. S. (2001). Distinct potassium channels on pain-sensing neurons. Proceedings of the National Academy of Sciences of the United States of America, 98(23), 13373–13378. doi:10.1073/pnas.231376298Find this resource:

Rau, K. K., Cooper, B. Y., & Johnson, R. D. (2006). Expression of TWIK-related acid sensitive K+ channels in capsaicin sensitive and insensitive cells of rat dorsal root ganglia. Neuroscience, 141(2), 955–963.Find this resource:

Ray, P., Torck, A., Quigley, L., Wangzhou, A., Neiman, M., Rao C., … Price, T. J. (2018). Comparative transcriptome profiling of the human and mouse dorsal root ganglia: An RNA-seq-based resource for pain and sensory neuroscience research. Pain, 159(7), 1325–1345.Find this resource:

Reinhold, A. K., Batti, L., Bilbao, D., Buness, A., Rittner, H. L., & Heppenstall, P. A. (2015). Differential transcriptional profiling of damaged and intact adjacent dorsal root ganglia neurons in neuropathic pain. PloS One, 10(4), e0123342. doi:10.1371/journal.pone.0123342Find this resource:

Rodriguez-Menchaca, A. A., Navarro-Polanco, R. A., Ferrer-Villada, T., Rupp, J., Sachse, F. B., Tristani-Firouzi, M., & Sanchez-Chapula, J. A. (2008). The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel. Proceedings of the National Academy of Sciences of the United States of America, 105(4), 1364–1368. doi:10.1073/pnas.0708153105Find this resource:

Rose, K., Ooi, L., Dalle, C., Robertson, B., Wood, I. C., & Gamper, N. (2011). Transcriptional repression of the M channel subunit Kv7.2 in chronic nerve injury. Pain, 152(4), 742–754. doi:10.1016/j.pain.2010.12.028Find this resource:

Royal, P., Andres-Bilbe, A., Avalos Prado, P., Verkest, C., Wdziekonski, B., Schaub, S., … Sandoz, G. (2019). Migraine-associated TRESK mutations increase neuronal excitability through alternative translation initiation and inhibition of TREK. Neuron, 101(2), 232–245 e236. doi:10.1016/j.neuron.2018.11.039Find this resource:

Roza, C., Castillejo, S., & Lopez-Garcia, J. A. (2011). Accumulation of Kv7.2 channels in putative ectopic transduction zones of mice nerve-end neuromas. Molecular Pain, 7, 58. doi:10.1186/1744-8069-7-58Find this resource:

Sachs, D., Cunha, F. Q., & Ferreira, S. H. (2004). Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway. Proceedings of the National Academy of Sciences of the United States of America, 101(10), 3680–3685. doi:10.1073/pnas.0308382101Find this resource:

Salinas, M., Duprat, F., Heurteaux, C., Hugnot, J. P., & Lazdunski, M. (1997). New modulatory alpha subunits for mammalian Shab K+ channels. The Journal of Biological Chemistry, 272(39), 24371–24379.Find this resource:

Sandoz, G., Douguet, D., Chatelain, F., Lazdunski, M., & Lesage, F. (2009). Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue. Proceedings of the National Academy of Sciences of the United States of America, 106(34), 14628–14633. doi:10.1073/pnas.0906267106Find this resource:

Sano, Y., Inamura, K., Miyake, A., Mochizuki, S., Kitada, C., Yokoi, H., … Furuichi, K. (2003). A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. The Journal of Biological Chemistry, 278(30), 27406–27412. doi:10.1074/jbc.M206810200Find this resource:

Schwartz, E. S., Xie, A., La, J. H., & Gebhart, G. F. (2015). Nociceptive and inflammatory mediator upregulation in a mouse model of chronic prostatitis. Pain, 156(8), 1537–1544.Find this resource:

Sheng, A., Hong, J., Zhang, L., Zhang, Y., & Zhang, G. (2018). The distributions of voltage-gated K(+) current subtypes in different cell sizes from adult mouse dorsal root ganglia. The Journal of Membrane Biology, 251(4), 573–579. doi:10.1007/s00232-018-0033-zFind this resource:

Silva, J. R., Lopes, A. H., Talbot, J., Cecilio, N. T., Rossato, M. F., Silva, R. L., … Cunha, T. M. (2017). Neuroimmune-glia interactions in the sensory ganglia account for the development of acute herpetic neuralgia. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 37(27), 6408–6422. doi:10.1523/JNEUROSCI.2233-16.2017Find this resource:

Smith, H. S. (2009). Calcineurin as a nociceptor modulator. Pain Physician, 12(4), E309–E318.Find this resource:

Staal, R. G. W., Khayrullina, T., Zhang, H., Davis, S., Fallon, S. M., Cajina, M., … Möller, T. (2017). Inhibition of the potassium channel KCa3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injury. European Journal of Pharmacology, 795, 1–7. doi:10.1016/j.ejphar.2016.11.031Find this resource:

Stotzner, P., Spahn, V., Celik, M. O., Labuz, D., & Machelska, H. (2018). Mu-opioid receptor agonist induces Kir3 currents in mouse peripheral sensory neurons—Effects of nerve injury. Frontiers in Pharmacology, 9, 1478. doi:10.3389/fphar.2018.01478Find this resource:

Takeda, M., Nasu, M., Kanazawa, T., & Shimazu, Y. (2015). Activation of GABA(B) receptors potentiates inward rectifying potassium currents in satellite glial cells from rat trigeminal ganglia: In vivo patch-clamp analysis. Neuroscience, 288, 51–58. doi:10.1016/j.neuroscience.2014.12.024Find this resource:

Takeda, M., Takahashi, M., Nasu, M., & Matsumoto, S. (2011). Peripheral inflammation suppresses inward rectifying potassium currents of satellite glial cells in the trigeminal ganglia. Pain, 152(9), 2147–2156. doi:10.1016/j.pain.2011.05.023Find this resource:

Takeda, M., Tanimoto, T., Nasu, M., & Matsumoto, S. (2008). Temporomandibular joint inflammation decreases the voltage-gated K+ channel subtype 1.4-immunoreactivity of trigeminal ganglion neurons in rats. European Journal of Pain (London, England), 12(2), 189–195. doi:10.1016/j.ejpain.2007.04.005Find this resource:

Talley, E. M., Solorzano, G., Lei, Q., Kim, D., & Bayliss, D. A. (2001). CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 21(19), 7491–7505. doi:10.1523/JNEUROSCI.21-19-07491.2001Find this resource:

Tamsett, T. J., Picchione, K. E., & Bhattacharjee, A. (2009). NAD+ activates KNa channels in dorsal root ganglion neurons. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 29(16), 5127–5134. doi:10.1523/JNEUROSCI.0859-09.2009Find this resource:

Tomasello, D. L., Hurley, E., Wrabetz, L., & Bhattacharjee, A. (2017). Slick (Kcnt2) sodium-activated potassium channels limit peptidergic nociceptor excitability and hyperalgesia. Journal of Experimental Neuroscience, 11, 1179069517726996. doi:10.1177/1179069517726996Find this resource:

Tsantoulas, C., Denk, F., Signore, M., Nassar, M. A., Futai, K., & McMahon, S. B. (2018). Mice lacking Kcns1 in peripheral neurons show increased basal and neuropathic pain sensitivity. Pain, 159(8), 1641–1651. doi:10.1097/j.pain.0000000000001255Find this resource:

Tsantoulas, C., Zhu, L., Shaifta, Y., Grist, J., Ward, J. P., Raouf, R., … McMahon, S. B. (2012). Sensory neuron downregulation of the Kv9.1 potassium channel subunit mediates neuropathic pain following nerve injury. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 32(48), 17502–17513. doi:10.1523/JNEUROSCI.3561-12.2012Find this resource:

Tsantoulas, C., Zhu, L., Yip, P., Grist, J., Michael, G. J., & McMahon, S. B. (2014). Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input. Experimental Neurology, 251, 115–126. doi:10.1016/j.expneurol.2013.11.011Find this resource:

Tulleuda, A., Cokic, B., Callejo, G., Saiani, B., Serra, J., & Gasull, X. (2011). TRESK channel contribution to nociceptive sensory neurons excitability: Modulation by nerve injury. Molecular Pain, 7, 30. doi:10.1186/1744-8069-7-30Find this resource:

Usoskin, D., Furlan, A., Islam, S., Abdo, H., Lonnerberg, P., Lou, D., … Ernfors, P. (2015). Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nature Neuroscience, 18(1), 145–153.Find this resource:

Viana, F., de la Pena, E., & Belmonte, C. (2002). Specificity of cold thermotransduction is determined by differential ionic channel expression. Nature Neuroscience, 5(3), 254–260.Find this resource:

Viatchenko-Karpinski, V., Ling, J., & Gu, J. G. (2018). Characterization of temperature-sensitive leak K(+) currents and expression of TRAAK, TREK-1, and TREK2 channels in dorsal root ganglion neurons of rats. Molecular Brain, 11(1), 40.Find this resource:

Vit, J. P., Jasmin, L., Bhargava, A., & Ohara, P. T. (2006). Satellite glial cells in the trigeminal ganglion as a determinant of orofacial neuropathic pain. Neuron Glia Biology, 2(4), 247–257.Find this resource:

Vit, J. P., Ohara, P. T., Bhargava, A., Kelley, K., & Jasmin, L. (2008). Silencing the Kir4.1 potassium channel subunit in satellite glial cells of the rat trigeminal ganglion results in pain-like behavior in the absence of nerve injury. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(16), 4161–4171. doi:10.1523/JNEUROSCI.5053-07.2008Find this resource:

Voets, T., Droogmans, G., Wissenbach, U., Janssens, A., Flockerzi, V., & Nilius, B. (2004). The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature, 430(7001), 748–754. doi:10.1038/nature02732Find this resource:

Vydyanathan, A., Wu, Z. Z., Chen, S. R., & Pan, H. L. (2005). A-type voltage-gated K+ currents influence firing properties of isolectin B4-positive but not isolectin B4-negative primary sensory neurons. The Journal of Neurophysiology, 93(6), 3401–3409. doi:10.1152/jn.01267.2004Find this resource:

Wada, Y., Yamashita, T., Imai, K., Miura, R., Takao, K., Nishi, M., … Nukada, T. (2000). A region of the sulfonylurea receptor critical for a modulation of ATP-sensitive K(+) channels by G-protein betagamma-subunits. The EMBO Journal, 19(18), 4915–4925. doi:10.1093/emboj/19.18.4915Find this resource:

Wu, S., Marie Lutz, B., Miao, X., Liang, L., Mo, K., Chang, Y. J., … Tao, Y. X. (2016). Dorsal root ganglion transcriptome analysis following peripheral nerve injury in mice. Molecular Pain, Mar 11, 12. doi:10.1177/1744806916629048Find this resource:

Wu, Y., Liu, Y., Hou, P., Yan, Z., Kong, W., Liu, B., … Ding, J. (2013). TRPV1 channels are functionally coupled with BK(mSlo1) channels in rat dorsal root ganglion (DRG) neurons. PloS One, 8(10), e78203. doi:10.1371/journal.pone.0078203Find this resource:

Wulf-Johansson, H., Amrutkar, D. V., Hay-Schmidt, A., Poulsen, A. N., Klaerke, D. A., Olesen, J., & Jansen-Olesen, I. (2010). Localization of large conductance calcium-activated potassium channels and their effect on calcitonin gene-related peptide release in the rat trigemino-neuronal pathway. Neuroscience, 167(4), 1091–1102. doi:10.1016/j.neuroscience.2010.02.063Find this resource:

Xing, J. L., & Hu, S. J. (1999). Relationship between calcium-dependent potassium channel and ectopic spontaneous discharges of injured dorsal root ganglion neurons in the rat. Brain Research, 838(1–2), 218–221.Find this resource:

Xu, D., Wu, X., Grabauskas, G., & Owyang, C. (2013). Butyrate-induced colonic hypersensitivity is mediated by mitogen-activated protein kinase activation in rat dorsal root ganglia. Gut, 62(10), 1466–1474. doi:10.1136/gutjnl-2012-302260Find this resource:

Yamamoto, Y., Hatakeyama, T., & Taniguchi, K. (2009). Immunohistochemical colocalization of TREK-1, TREK-2 and TRAAK with TRP channels in the trigeminal ganglion cells. Neuroscience Letters, 454(2), 129–133. doi:10.1016/j.neulet.2009.02.069Find this resource:

Yang, E. K., Takimoto, K., Hayashi, Y., de Groat, W. C., & Yoshimura, N. (2004). Altered expression of potassium channel subunit mRNA and alpha-dendrotoxin sensitivity of potassium currents in rat dorsal root ganglion neurons after axotomy. Neuroscience, 123(4), 867–874. doi:10.1016/j.neuroscience.2003.11.014Find this resource:

Yang, Y., Li, S., Jin, Z. R., Jing, H. B., Zhao, H. Y., Liu, B. H., … Xing, G. G. (2018). Decreased abundance of TRESK two-pore domain potassium channels in sensory neurons underlies the pain associated with bone metastasis. Science Signaling, 11(552). doi:10.1126/scisignal.aao5150Find this resource:

Yellen, G. (2002). The voltage-gated potassium channels and their relatives. Nature, 419(6902), 35–42. doi:10.1038/nature00978Find this resource:

Yoo, S., Liu, J., Sabbadini, M., Au, P., Xie, G. X., & Yost, C. S. (2009). Regional expression of the anesthetic-activated potassium channel TRESK in the rat nervous system. Neuroscience Letters, 465(1), 79-84. doi:10.1016/j.neulet.2009.08.062Find this resource:

Yoshimura, M., & North, R. A. (1983). Substantia gelatinosa neurones hyperpolarized in vitro by enkephalin. Nature, 305(5934), 529–530.Find this resource:

Yu, T., Li, L., Liu, H., Li, H., Liu, Z., & Li, Z. (2018). KCNQ2/3/5 channels in dorsal root ganglion neurons can be therapeutic targets of neuropathic pain in diabetic rats. Molecular Pain, 14, 1744806918793229. doi:10.1177/1744806918793229Find this resource:

Yuan, J., Wen, J., Wu, S., Mao, Y., Mo, K., Li, Z., … Tao, Y. X. (2019). Contribution of dorsal root ganglion octamer transcription factor 1 to neuropathic pain after peripheral nerve injury. Pain, 160, 375–384. doi:10.1097/j.pain.0000000000001405Find this resource:

Zemel, B. M., Ritter, D. M., Covarrubias, M., & Muqeem, T. (2018). A-type KV channels in dorsal root ganglion neurons: Diversity, function, and dysfunction. Frontiers in Molecular Neuroscience, 11, 253. doi:10.3389/fnmol.2018.00253Find this resource:

Zerangue, N., Schwappach, B., Jan, Y. N., & Jan, L. Y. (1999). A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Neuron, 22(3), 537–548.Find this resource:

Zhang, F. X., Gadotti, V. M., Souza, I. A., Chen, L., & Zamponi, G. W. (2018). BK potassium channels suppress cavalpha2delta subunit function to reduce inflammatory and neuropathic pain. Cell Reports, 22(8), 1956–1964. doi:10.1016/j.celrep.2018.01.073Find this resource:

Zhang, H., & Dougherty, P. M. (2014). Enhanced excitability of primary sensory neurons and altered gene expression of neuronal ion channels in dorsal root ganglion in paclitaxel-induced peripheral neuropathy. Anesthesiology, 120(6), 1463–1475. doi:10.1097/ALN.0000000000000176Find this resource:

Zhao, H., Sprunger, L. K., & Simasko, S. M. (2010). Expression of transient receptor potential channels and two-pore potassium channels in subtypes of vagal afferent neurons in rat. American Journal of Physiology. Gastrointestinal and Liver Physiology, 298(2), G212–G221.Find this resource:

Zhao, X., Tang, Z., Zhang, H., Atianjoh, F. E., Zhao, J. Y., Liang, L., … Tao, Y. X. (2013). A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nature Neuroscience, 16(8), 1024–1031. doi:10.1038/nn.3438Find this resource:

Zhao, J. Y., Liang, L., Gu, X., Li, Z., Wu, S., Sun, L., … Tao, Y. X. (2017). DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nature Communications, 8, 14712. doi:10.1038/ncomms14712Find this resource:

Zheng, Q., Fang, D., Liu, M., Cai, J., Wan, Y., Han, J. S., & Xing, G. G. (2013). Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model. Pain, 154(3), 434–448. doi:10.1016/j.pain.2012.12.005Find this resource:

Zhou, J., Yang, C. X., Zhong, J. Y., & Wang, H. B. (2013). Intrathecal TRESK gene recombinant adenovirus attenuates spared nerve injury-induced neuropathic pain in rats. Neuroreport, 24(3), 131–136. doi:10.1097/WNR.0b013e32835d8431Find this resource:

Zhou, J., Yao, S. L., Yang, C. X., Zhong, J. Y., Wang, H. B., & Zhang, Y. (2012). TRESK gene recombinant adenovirus vector inhibits capsaicin-mediated substance P release from cultured rat dorsal root ganglion neurons. Molecular Medicine Reports, 5(4), 1049–1052. doi:10.3892/mmr.2012.778Find this resource:

Zoga, V., Kawano, T., Liang, M. Y., Bienengraeber, M., Weihrauch, D., McCallum, B., … Sarantopoulos, C. (2010). KATP channel subunits in rat dorsal root ganglia: Alterations by painful axotomy. Molecular Pain, 6, 6. doi:10.1186/1744-8069-6-6Find this resource: