Sensory Signaling Pathways in Inflammatory and Neuropathic Pain
Abstract and Keywords
Sensory neuron sensitivity is modulated by a large variety of mediators that can activate a plethora of signaling cascades. These signaling cascades allow sensory neurons to show remarkable plasticity in response to injury and inflammation. The understanding of intracellular signaling mechanisms that regulate sensory neuron function downstream of receptor–ligand interactions or electrical activity is still at a relatively developing stage. This chapter highlights what is known about some of the components of classical intracellular signal transduction cascades, such as cyclic adenosine monophosphate (cAMP) and downstream cAMP sensors, mitogen-activated protein kinases, and others in regulating sensory neuron function. How these transduction cascades may contribute to the initiation, maintenance, or even resolution of inflammatory and neuropathic pain is discussed. Moreover, the focus is on how intracellular signaling cascades themselves are subject to plasticity and how this plasticity may underlie the development of chronic pain.
Pain associated with inflammation or lesions to the nervous system often becomes persistent. Pathological pains manifest as spontaneous pain, hyperalgesia, and allodynia. The majority of inflammatory pain is observed in patients suffering from rheumatic diseases or inflammatory bowel diseases. Neuropathic pain is often caused by injury, surgery, diabetes mellitus, amputation, viral infection, trauma, or stroke, which damage the peripheral nervous system (peripheral nerves, dorsal root ganglia [DRG], and dorsal roots) or the central nervous system (CNS). Inflammatory pain and neuropathic pain are generally considered different entities of pain, each characterized by distinct neurochemical changes in the spinal cord and DRG. However, neuropathic pain also shares features of inflammatory pain, which makes the discrimination between inflammatory, neuropathic, or any type of pain sometimes difficult. For this reason, the International Association of the Study of Pain (IASP) introduced a new term in 2017, nociplastic pain, to indicate pain that arises from altered nociception, despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain (Aydede & Shriver, 2018). Importantly, irrespective of the type of pain, inflammation or inflammatory reactions are likely central to the initiation or maintenance of these pains. For example, after nerve injury, inflammatory mediators are produced. Conversely, chronic inflammatory processes may damage nerves in the long term. Despite the differences between inflammatory and neuropathic pain, sensory neurons respond to the inflammation or damage via the activation of specific signal transduction pathways that initiate or maintain neuroplastic changes contributing to pathological pain. In this chapter, we discuss intracellular signaling events in sensory neurons that contribute to the pathophysiology of neuropathic and inflammatory pain. Although the main focus is on signaling pathways in primary sensory neurons, to some extent signaling events in neurons in the spinal cord dorsal horn that receive peripheral input are discussed as well.
Intracellular signal propagation by passive diffusion is not suitable in neurons, which may have axons ranging from a centimeter to a meter in humans, because diffusion has a limited range of tens of micrometers. Thus, sensory neurons have sophisticated mechanisms and compartmentalized signaling hubs that convey important information from the outside and aid neurons to adapt and tune their ability to transduce and propagate pain signals (Gumy et al., 2017; Kholodenko, 2003; Wiegert, Bengtson, & Bading, 2007). Sensory neurons express a range of proteins that are able to convey and transduce extracellular cues. Primary sensory neurons consist of different subtypes, and recent advances in single-cell RNA sequencing have allowed for an effective strategy for dissecting sensory responsive cells into distinct neuronal types (C. L. Li et al., 2016; Usoskin et al., 2015). Intriguingly, the resulting catalogue illustrates the diversity of sensory neurons and has identified variability in the presence (and absence) of some key signaling molecules (Figure 1).
Although current single-cell RNA sequence analyses only provide a partial transcriptome and do not tell us anything about protein levels, these data sets indicate that neuron subsets likely have their own unique signaling machinery that allows them to initiate specific responses to extracellular cues. These responses, mediated by signaling molecules, allow for transient adaptation (e.g., sensitization of ion channels that are causal to hyperalgesia). Moreover, these signaling events may also be the initiators of long-term (transcriptional) changes in neurons that underlie pathological pain.
In this chapter, we address classical intracellular signal transduction pathways that are able to produce and tune pain signals. We discuss how these different pathways may diverge to cause transient pain hypersensitivity, as well as long-lasting plastic changes in sensory neurons that may contribute to chronic pain. Although myriad pro-inflammatory mediators and their receptors can cause activation of a range of signaling pathways in sensory neurons, we focus on the core components of classical intracellular signaling pathways, such as cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) and protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and some other kinases.
Cyclic Adenosine Monophosphate
Cyclic adenosine monophosphate is one of the first second messengers identified in regulating pain sensitivity downstream of receptor–ligand binding. Many different inflammatory mediators, including serotonin, endothelin, epinephrine, and prostaglandin, modulate nociception by acting on G protein–coupled receptors (GPCRs) in sensory neurons. These GPCRs couple to the Gαs that, on ligand binding, activate adenylyl cyclase (AC), causing an increase in intracellular cAMP levels. Various studies indicated that increased neuronal excitability is the result of the activation of GPCRs, including those that couple to AC. GPCR activation modulates sensory transducers and voltage-gated ion channels present on sensory neurons (Figure 2).
For example, the best known inflammatory agent that increases pain sensitivity, the prostanoid prostaglandin E2 (PGE2), increases intracellular cAMP levels and induces hyperalgesia in humans and rodents (Collier & Schneider, 1972; Ferreira, Nakamura, & de Abreu Castro, 1978). This acute hyperalgesia is blocked by co-injection of the inactive cAMP analogue Rp-cAMP, which prevents the release of the catalytic subunit by maintaining the regulatory subunit of PKA in a locked conformation. In contrast, inhibiting the phosphodiesterase (PDE) 4, which metabolizes cAMP, enhances PGE2-induced cAMP and aggravates PGE2-induced hyperalgesia (F. Q. Cunha, Teixeira, & Ferreira, 1999; Taiwo & Levine, 1991). Moreover, hyperalgesia can be induced by injection of cAMP analogues (e.g., dibutyryl(db)-cAMP and 8-Bromo(br)-cAMP) or AC activators such as forskolin (Eijkelkamp et al., 2010; Ferreira, Lorenzetti, & De Campos, 1990; Taiwo & Levine, 1991).
Thus, generation of cAMP initiates the development of sensory hypersensitivity. However, cAMP can also contribute to maintaining hyperalgesia. In various models of chronic neuropathic pain, cyclooxygenase 2 (COX2) and PGE2 are chronically upregulated and contribute to neuropathic pain conditions (Ma & Quirion, 2008; St-Jacques & Ma, 2011). The competitive inhibitor of PKA, Rp-cAMP, reduces established inflammatory hyperalgesia (Aley & Levine, 1999; Taiwo & Levine, 1991), and inhibition of AC reduces neuronal hyperexcitability induced by nerve injury (Z. J. Huang et al., 2012). Importantly, mice deficient in AC activity are protected against inflammatory pain (Wei et al., 2002).
In agreement with the pain-promoting effects of cAMP, various mediators that have analgesic actions (e.g., opioids, gamma-aminobutyric acid B [GABAB], and neuropeptide Y [NPY]), activate Gi-coupled GPCRs that reduce cAMP by inhibiting AC (Levine & Taiwo, 1989; Natura et al., 2013; Schuler et al., 2001; Smith, Moran, Abdulla, Tumber, & Taylor, 2007). As an example, opioid ligands, which are well known for their pain-inhibiting effects, inhibit voltage-gated calcium channels (VGCCs) by reducing cAMP levels (C. Stein, Schafer, & Machelska, 2003). The majority of effects on Gi-coupled GPCRs are thought to be mediated by inhibition of the canonical cAMP pathway. However, the Gβ/γ protein also conveys signals from µ opioid, GABAB, and NPY Gi-coupled GPCR by inhibiting activity of ion channels, for example, the transient receptor potential (TRP) melastatin 1 (TRPM1) (Quallo, Alkhatib, Gentry, Andersson, & Bevan, 2017).
Overall, cAMP and mediators that induce cAMP are involved in the induction and maintenance of hyperalgesia. Downstream signal transduction of cAMP has long been held synonymous with the activation of PKA, and as such, most research in the pain field has focused on PKA. However, in 1998, two groups independently discovered the cAMP sensor exchange protein activated by cAMP (Epac) (de Rooij et al., 1998; H. Kawasaki et al., 1998). After the identification of Epacs, increasing evidence has indicated an additional role of Epac signaling in chronic pain (see the section that follows on Epac). In addition to mediating its effects through these cAMP sensors, cAMP can alter sensory neuron function by gating of the hyperpolarization-activated cation channels (HCNs). HCN2 is expressed in more than half of the small nociceptive neurons and is sensitive to cAMP. cAMP activates HCN2 and promotes the inward current that could drive repetitive firing in sensory neurons (Emery, Young, Berrocoso, Chen, & McNaughton, 2011), although some effect may be mediated through PKA (Herrmann et al., 2017). Addition of AC activators (e.g., forskolin, PGE2) to sensory neurons increases action potential firing, which does not occur in neurons lacking HCN2. Importantly, inflammatory pain and neuropathic pain are attenuated in mice with specific deletion of HCN2 in nociceptors. Thus, cAMP may contribute to chronic pain by gating HCN2 channels.
Protein Kinase A
By using specific inhibitors, Ferreira and Levine provided the first evidence that PKA is involved in controlling inflammatory hyperalgesia (Aley & Levine, 1999; F. Q. Cunha et al., 1999; Taiwo & Levine, 1991). More recently, a nociceptor-specific contribution of PKA to inflammatory pain was unveiled because Complete Freund’s Adjuvant (CFA)–induced mechanical and thermal hyperalgesia is ablated in nociceptor-specific (Nav1.8), PKA-inhibited mutants (Herrmann et al., 2017). Intraplantar injection of PGE2 induced hyperalgesia (Taiwo & Levine, 1989, 1991) completely blocked by PKA inhibitors H89 and Rp-cAMP (Aley & Levine, 1999). In line with these findings, the regulatory subunit of PKA, RIIβ, regulates nociceptive processing in the terminals of small-diameter primary afferent fibers stimulated with pain-sensitizing inflammatory mediators and activators of PKA (Isensee et al., 2014). Moreover, epinephrine, a hormone and neurotransmitter that is released on stressful events and following tissue trauma and peripheral neuropathies (Janig, Levine, & Michaelis, 1996), induces hyperalgesia that in part is blocked by PKA inhibition (X. Chen & Levine, 2005; H. Wang et al., 2011). Similarly, intradermal injections of mediators that signal through Gs-coupled GPCRs (e.g., serotonin, calcitonin gene–related peptide [CGRP], adenosine) lower thresholds for mechanical and thermal stimuli in a cAMP- and PKA-dependent fashion (Cornelison, Hawkins, & Durham, 2016; Taiwo, Heller, & Levine, 1992; Taiwo & Levine, 1990). Mediators produced during inflammation, such as tumor necrosis factor (TNF) or interleukin (IL) 1β, which do not activate receptors directly coupled to AC, can also produce hyperalgesia via a route that at least in part depends on activation of PKA (M. J. Kim et al., 2014; J. M. Zhang, Li, Liu, & Brull, 2002). Application of TNF to DRGs elicits neuronal discharges in C fibers and enhances electrical excitability that is blocked by the PKA inhibitors H89 or Rp-cAMP (J. M. Zhang et al., 2002). Intriguingly, signaling pathways involved in IL1β-induced hypersensitivity appear to differ between sensory neuron subsets. In large-diameter primary afferent nerve fibers, PKA contributes to IL1β-induced mechanical hypersensitivity; in small-diameter primary afferent nerves, PKC mediates IL1-induced thermal hyperalgesia (M. J. Kim et al., 2014). How IL-1β or TNF signaling elevates cAMP in these neurons still needs to be elucidated. Possibly, elevated cytosolic calcium levels activate calcium-activated ACs, such as AC1 and AC8. Alternatively, cAMP elevation may be triggered through indirect production of inflammatory mediators, such as PGE2.
With the use of pharmacological and genetic approaches, various groups have tried to identify whether cAMP–PKA signaling also contributes to neuropathic pain. Mice deficient for AC5 do not develop the same magnitude of mechanical allodynia in models of neuropathic pain compared to wild-type mice (K. S. Kim et al., 2007). Moreover, pharmacological inhibition of PKA reduces neuronal hyperexcitability, hyperalgesia, and mechanical allodynia after nerve damage induced by partial sciatic nerve ligation, spinal cord injury, DRG compression, and bone cancer (Z. J. Huang et al., 2012; Liou, Liu, Hsin, Yang, & Lui, 2007; X. J. Song, Wang, Gan, & Walters, 2006; G. Q. Zhu, Liu, He, Liu, & Song, 2014). However, these studies did not distinguish between the role of PKA in primary sensory neurons or the spinal cord. Spinal cord injury induces persistent electrical hypersensitivity in primary sensory neurons that requires continuing AC and PKA activity, indicating a role for PKA in primary sensory neurons (Bavencoffe et al., 2016). However, development of neuropathic pain in transgenic mice with a sensory neuron–specific PKA mutant (dominant negative mutation in RIα locus, which prevents cAMP binding) was not affected (Malmberg et al., 1997). In line with these studies, nerve injury–induced allodynia developed normal in Nav1.8 nociceptor-specific PKA mutant mice. However, the contribution of Nav1.8 neurons to neuropathic pain is limited (Abrahamsen et al., 2008).
These data suggest that reduced neuropathic pain that is observed after intrathecal injection of a PKA inhibitor is likely caused by postsynaptic PKA inhibition. Consistent with this notion is the finding that PKA has been implicated in the development of the early phase of spinal long-term potentiation (LTP) in C-fiber synapses that is induced by noxious electrical and pungent stimuli (X. G. Liu & Zhou, 2015).
Signaling by PKA may contribute in various ways to the development and maintenance of pathological pain (Figure 2). Clearly, PKA has the ability to phosphorylate various ion channels that affect neuronal transduction and excitability. For example, PKA can phosphorylate transient receptor potential channel vanilloid 1 (TRPV1), a heat-activated ion channel, at Ser-116, Ser-502, Thr-144, and Thr-370 to promote sensitization or modulate its activity (Bhave et al., 2002; Mohapatra & Nau, 2003; Rathee et al., 2002). Moreover, sensitization of sensory neurons by PGE2 or forskolin requires anchoring of both PKA and AC to TRPV1 by AKAP79/150 (Efendiev, Bavencoffe, Hu, Zhu, & Dessauer, 2013). Other transduction channels that are regulated by PKA activation include the mechanosensitive channels Piezo2 (Borbiro & Rohacs, 2017) and TRPA1 (Meents, Fischer, & McNaughton, 2017) and likely various other channels. The functional relevance of the sensitization of TRPA1 is highlighted by data showing that reduction in TRPA1 expression or TRPA1 function blockade with a specific channel blocker attenuates hyperalgesia induced by PKA and PGE2 (Dall’Acqua et al., 2014).
The PKA-mediated regulation of sensory neuron excitability has mostly focused on voltage-gated sodium channels. Sodium channels have multiple sites for phosphorylation by PKA, and phosphorylation of these sites modulates peripheral neuron excitability (Bevan & Storey, 2002). PKA activation with inflammatory mediators (PGE2), AC activators, or cAMP analogues increases excitability of sensory neurons through enhancing sodium channel currents by causing (a) hyperpolarizing shifts in activation and steady-state inactivation of tetrodotoxin (TTX)–resistant Na+ current; (b) increasing the rates of activation and deactivation of sodium channels; and (c) promoting the trafficking of the TTX-resistant sodium channels (e.g., Nav1.8) to the cell membrane (Bevan & Storey, 2002; Chahine & O’Leary, 2014; England, Bevan, & Docherty, 1996; Fitzgerald, Okuse, Wood, Dolphin, & Moss, 1999; Gold, Levine, & Correa, 1998; Gold, Reichling, Shuster, & Levine, 1996; C. Liu, Li, Su, & Bao, 2010). Continuous activation of PKA and its effect on the TTX-resistant sodium channel Nav1.8 are associated with persistent inflammatory pain (Villarreal et al., 2009). In contrast to Nav1.8, PKA activation surprisingly reduces the TTX-sensitive sensory neuron–specific sodium channel Nav1.7 currents (Vijayaragavan, Boutjdir, & Chahine, 2004). Intriguingly, cAMP-mediated signaling modulates human Nav1.7 by regulating alternative splicing, which affects the proportion of Nav1.7 splice variants, each having different biophysical properties (Chatelier, Dahllund, Eriksson, Krupp, & Chahine, 2008).
Evidence of PKA regulation of other channels that influence sensory neuron excitability is less evident. Some reports showed that PGE2 inhibits an outward potassium current in sensory neurons via activation of PKA, thereby partly inhibiting delayed rectifier-like potassium current (Evans, Vasko, & Nicol, 1999). Moreover, PKA stimulation of DRG neurons causes hyperexcitability consistent with a reduction of K+ current (X. J. Song et al., 2006; Zheng, Walters, & Song, 2007), likely through internalization of the slack KNa channels (Nuwer, Picchione, & Bhattacharjee, 2010). It is likely that cAMP–PKA signaling also modulates other channels, such as voltage-gated potassium and calcium channels critically involved in neuronal excitability.
Exchange Factor Activated by cAMP
Activation of the cAMP sensor Epac, also known as cAMP-regulated guanine nucleotide exchange factor, stimulates the exchange of guanosine diphosphate (GDP) bound to Rap for guanosine triphosphate (GTP). Rap–GTP activation is upstream of various other effector proteins that affect the cytoskeleton, phospholipases, and MAPKs (Figure 2). The first evidence for a role of Epac in pain signaling came from Levine and coworkers 7 years after the discovery of Epacs. They showed that a selective Epac activator 8-(4-chlorophenylthio)-2′-O-methyl-cAMP (8-pCPT) induced long-lasting mechanical hypersensitivity (T. B. Hucho, Dina, & Levine, 2005). Two isoforms of Epac exist (Epac1 and Epac2), and expression of both is enhanced in DRGs during chronic inflammatory pain or after incision-induced tissue injury (Gu, Li, Chen, & Huang, 2016; Matsuda, Oh-Hashi, Yokota, Sawa, & Amaya, 2017; H. Wang et al., 2013). In vitro nerve growth factor (NGF) selectively increases Epac2 expression (Vasko et al., 2014). Epac1 expression was increased in the DRG in mouse models of neuropathic pain (Bangash et al., 2018; Eijkelkamp et al., 2013). In mice lacking Epac1 (Epac1−/−), development of nerve damage–induced mechanical allodynia was profoundly attenuated (Eijkelkamp et al., 2013). Similarly, Epac1−/− mice were protected against CFA-induced mechanical hyperalgesia (Singhmar et al., 2016). Transient knockdown of Epac1 also reduced established CFA-induced persistent inflammatory and postoperative pain (S. Cao, Bian, Zhu, & Shen, 2016; H. Wang et al., 2013). These combined data indicate that Epac1 is predominantly required for maintenance of persistent pain. This is further supported by data showing that general Epac inhibitors (e.g., ESI-09) or specific Epac isoform inhibitors (CE3F4, HJC0350) attenuated inflammatory and bone cancer pain (Gu, Li, et al., 2016; Singhmar et al., 2016; G. Q. Zhu et al., 2014). Moreover, an orally active Epac inhibitor reversed the loss of intraepidermal nerve fibers and mechanical allodynia in a model of chemotherapy-induced neuropathy (Singhmar et al., 2018).
Both Epac isoforms can contribute to sensitization of sensory neurons (Eijkelkamp et al., 2013; Vasko et al., 2014), but until now the majority of studies investigated Epac1. Epac1 activation in sensory neurons enhanced mechanotransduction mediated by the mechanosensitive channel Piezo2 (Eijkelkamp et al., 2013; Singhmar et al., 2016). In vivo knockdown of Piezo2 in sensory neurons reduced mechanical hypersensitivity induced by either intraplantar injection of the Epac-selective cAMP analogue 8-pCPT or induced by nerve damage (Eijkelkamp et al., 2013). Moreover, Epac activation in sensory neurons sensitized P2X3R through activating protein kinase C alpha (PKCα), rendering neurons more sensitive to adenosine triphosphate (ATP) released from damaged or inflamed tissues (Gu, Li, et al., 2016; Gu, Wang, Li, & Huang, 2016). Finally, selective activation of Epacs increased the number of action potentials generated by a ramp of depolarizing current and increased the evoked release of CGRP from rat sensory neurons (Shariati, Thompson, Nicol, & Vasko, 2016).
Epac1 signaling is controlled by the G protein–coupled receptor kinase 2 (GRK2), a kinase that has functions extending to regulating GPCRs. GRK2 phosphorylates Epac1 on serine-108, reducing Epac1-to-Rap1 signaling and preventing Epac1-mediated sensitization of Piezo2 (Singhmar et al., 2016). Peripheral inflammation reduces GRK2 expression levels in isolectin B4–positive (IB4+) sensory neurons (H. Wang et al., 2013; H. J. Wang, Gu, Eijkelkamp, Heijnen, & Kavelaars, 2018), releasing GRK2-dependent inhibition of Epac1 signaling, leading to enhanced sensitization. Reduced GRK2 expression in sensory neurons prevents resolution of transient inflammatory pain, causing long-term enhancement of this pain (Eijkelkamp et al., 2010; Ferrari et al., 2012; H. Wang et al., 2011, 2013; H. J. Wang et al., 2018). In contrast, overexpressing GRK2 in sensory neurons alleviated persistent inflammatory pain (H. Wang et al., 2013; H. J. Wang et al., 2018). Thus, controlling GRK2 expression/activity in sensory neurons is a molecular mechanism for controlling Epac1 activity in neurons, regulating the duration of pain.
Protein Kinase C
The mammalian PKC family consists of 10 serine/threonine kinases that are grouped into three classes (conventional, novel, atypical) based on their domain structure and calcium and diacylgycerol dependence. The α, βI, βII, and γ isoforms are the conventional PKCs and are calcium and diacylglycerol dependent, while the novel PKC isoforms (δ, ε, η, and θ) are calcium independent but diacylglycerol dependent. The atypical PKC isozymes ξ and λ/ι are calcium and diacylglycerol independent. In primary sensory afferents, PKC α, βI, βII, δ, ε, and ξ isozymes have been identified, while PKC α, βI, βII, and γ are predominantly found in the superficial laminae of the dorsal spinal cord (Velazquez, Mohammad, & Sweitzer, 2007).
Since the early 1980s, the translocation of PKCs from the cytosol to the membrane has served as the hallmark for PKC activation (Kraft & Anderson, 1983). The first studies in the 1980s showed that in vitro PKC activation depolarized unmyelinated afferent neurons (Dray, Bettaney, Forster, & Perkins, 1988; Rang & Ritchie, 1988). Moreover, PKC activators enhanced currents activated by noxious thermal stimuli and sensitized sensory neurons (Cesare & McNaughton, 1996; Schepelmann, Messlinger, & Schmidt, 1993), indicating that PKC activation regulates sensory transduction. Indeed, activators of PKC, either given in vitro or in vivo, increased mechanically activated membrane current and caused behavioral sensitization to mechanical stimulation, likely due to insertion of mechanically activated channels into the plasma membrane (Di Castro, Drew, Wood, & Cesare, 2006). The mechanism by which PKC enhances mechanotransduction is different from that of NGF-induced enhancement of mechanotransduction, which is transcriptionally regulated (Di Castro et al., 2006). Inflammatory mediators that activate not only PKC, but also PKC activation alone, are sufficient to enhance transduction through sensitizing the mechanosensitive channel Piezo2 (Dubin et al., 2012). Reports have also shown that PKC sensitizes various other ion channels, including TRPV1 and sodium and potassium channels (Baker, 2005; Dubin et al., 2012; Mo et al., 2011; Numazaki, Tominaga, Toyooka, & Tominaga, 2002). PKCε phosphorylates the TRPV1 receptor on Ser502 and Ser800, an event responsible for the potentiation of capsaicin-evoked currents (Mandadi et al., 2006; Numazaki et al., 2002). Preventing phosphorylation of Ser800 blocks hypersensitivity to capsaicin, heat, and acid induced by phorbol 12-myristate 13-acetat (PMA), a PKC activator (S. Wang, Joseph, Ro, & Chung, 2015). Similarly, other PKC isoforms, such as PKCδ and PKCμ, may also play a role in TRPV1 sensitization (Obreja et al., 2005; Y. Wang et al., 2004). Next to a role in controlling afferent neuron excitability and transduction, PKC activation also modulates synaptic transmission. PKC activation enhances substance P and CGRP release and potentiates potassium-, chemokine-, and capsaicin-stimulated release of these neuropeptides (Barber & Vasko, 1996; Frayer, Barber, & Vasko, 1999; Malcangio, Fernandes, & Tomlinson, 1998; X. Qin, Wan, & Wang, 2005).
In vivo activation of PKC in nociceptors produces hyperalgesia, and various PKC inhibitors have antinociceptive effects in models of inflammatory and neuropathic pain (Souza et al., 2002; Velazquez et al., 2007). However, the most compelling evidence supports a role for PKCε isoform in nociceptors and pain. In response to inflammatory mediators such as bradykinin, substance P, and epinephrine, PKCε translocated to the plasma membrane of nociceptors (T. Hucho & Levine., 2007). Similarly, in the presence of persistent inflammatory pain, PKCε was phosphorylated in sensory neurons (Y. Zhou, Li, & Zhao, 2003). Inhibition of PKCε with inhibitors or genetically using PKCε null mutant mice limited inflammatory hyperalgesia and nociceptor sensitization (Khasar et al., 1999). Activation of PKCε with receptor for activated C kinase (ψεRACK) induces mechanical allodynia that is dependent on downstream mitochondrial mechanisms and an intact cytoskeleton (Dina, McCarter, de Coupade, & Levine, 2003; Joseph & Levine, 2010b). PKCε can phosphorylate the sodium channel Nav1.8, which increases channel function and produces mechanical hyperalgesia in mice (Wu et al., 2012). PKCε activation is also a key signaling molecule in tuning nociceptor function and plasticity. First, PKCε activation is sufficient to induce priming of nociceptors, inducing a remarkable susceptibility of nociceptors to normally subthreshold noxious or inflammatory inputs, which now cause severely prolonged pain (T. Hucho & Levine, 2007; Joseph, Parada, & Levine, 2003). In addition, PKCε is activated downstream of cAMP signaling after priming of sensory neurons with inflammatory mediators; in naïve conditions, this cAMP pathway does not activate PKCε. Intriguingly, the cAMP sensor Epac1 is thought to form the bridge between cAMP and PKCε signaling in these primed nociceptors (Eijkelkamp, Singhmar, Heijnen, & Kavelaars, 2015; T. Hucho & Levine, 2007; T. B. Hucho et al., 2005). These findings highlight that PKCε may be central to the switch from acute to chronic pain development (see more details in the section Sensory Neuron Signaling and Hyperalgesic Priming). Although PKCε is the best studied PKC isoform with respect to pain, there are also some studies that indicated that other isoforms, such as PKCα, contribute to inflammatory pain (Gold & Flake, 2005; Gu, Li, et al., 2016).
The role of PKC signaling is not limited to inflammatory pain. In a rodent model of painful diabetic neuropathy, PKC inhibitors decreased hyperalgesia and the hyperresponsiveness of C-afferent neurons (Ahlgren & Levine, 1994). Allodynia induced by chemotherapy (vincristine) was PKCε dependent, although only in males (Joseph & Levine, 2003). In a different model, paclitaxel-induced neuropathy, allodynia was not only dependent on PKCε, but also on conventional and novel PKC isoforms PKCβII and PKCδ (He & Wang, 2015; Hua, Chen, & Yaksh, 1999). In vitro, paclitaxel caused translocation of all three isoforms (PKCβII, PKCδ, and PKCε) to the plasma membrane (He & Wang, 2015; Miyano et al., 2009), but with the activation of PKCβII most prominent in IB4-negative neurons. Although all three isoforms contributed to paclitaxel-induced allodynia, only inhibition of PKCβII and PKCδ blocked the spontaneous pain induced by paclitaxel, and inhibition of PKC βII had the most profound effects (He & Wang, 2015).
Calcium ions are the most ubiquitous and pluripotent cellular signaling molecules, and major neuronal functions are regulated by Ca2+, including neurotransmitter release, excitability, neuron growth, differentiation, death, neuronal plasticity, and gene expression (Anglister, Farber, Shahar, & Grinvald, 1982; Ekstrom, 1995; Ghosh & Greenberg, 1995). Ca2+ is key in pain signaling, particularly in facilitated pain states. Action potentials elevate cytosolic Ca2+ in primary afferent neurons that persists for seconds to minutes. The elevated Ca2+ levels provide an integrative and memory process very early in somatic sensory signaling.
Intracellular Ca2+ acts as a second messenger and activates various calcium-dependent enzymes, kinases, and phosphatases (e.g., PKC, calmodulin); modulates ion channel activity or localization; increases neurotransmitter release; and regulates expression of a wide variety of gene targets (Bading, Hardingham, Johnson, & Chawla, 1997; Burgoyne & Haynes, 2015; Fields, Lee, & Cohen, 2005; Ji et al., 1996) (Figures 2 and 3). The physiological impact of Ca2+ in pain signaling is clearly dependent on the subcellular distribution of the calcium source, the sinks, and the calcium effectors. Various studies examining calcium regulation in different pain models have provided evidence for specific patterns in the regulation of calcium (Xu & Yaksh., 2011). In models of nerve injury, neuronal excitability of DRG neurons was increased. This neuronal hyperexcitability was associated with decreased resting calcium concentrations in injured DRG neurons, less recruitment of calcium-sensitive potassium channels, and reduced evoked or voltage-dependent calcium transients in injured putative nociceptive DRG neurons; in surrounding uninjured neurons, these calcium currents were enhanced (Fuchs, Rigaud, Sarantopoulos, Filip, & Hogan, 2007; Fuchs, Lirk, Stucky, Abram, & Hogan, 2005; Hagenston & Simonetti, 2014; Hogan, 2007; J. Yang et al., 2018).
In models of inflammatory pain, resting Ca2+ concentrations are increased, and depolarization-evoked calcium transients are larger and decay more slowly in sensory neurons innervating the inflamed tissue (Hagenston & Simonetti, 2014; Lu & Gold, 2008; Lu, Zhang, Luo, & Gold, 2010; Waxman & Zamponi, 2014). The increased excitability of sensory neurons during inflammation involves changes in calcium signaling within sensory terminals and presynaptic endings (Basbaum, Bautista, Scherrer, & Julius, 2009; Katz & Gold, 2006).
The Ca2+ signals are provided through several mechanisms. Noxious stimuli increase intracellular Ca2+ levels in sensory neurons through opening transduction channels. Moreover, elevated intracellular Ca2+ levels are triggered by ligand-gated ion channels (e.g., ATP-responsive purinoreceptors; P2XRs) and VGCCs expressed in sensory neurons. Aberrant calcium channel expression and function contribute to chronic neuropathic inflammatory pain (Bourinet et al., 2014; Fernyhough & Calcutt, 2010; Hagenston & Simonetti, 2014). In addition, changes in cytosolic calcium concentrations in sensory neurons can be mediated by the release of calcium from intracellular stores following activation of GPCRs (by inflammatory mediators such as bradykinin, chemokines) or receptor tyrosine kinases (RTKs) and subsequent activation of inositol trisphosphate receptors (IP3Rs) in the endoplasmic reticulum (ER). Finally Ca2+ transport out of the mitochondrial lumen via the mitochondrial sodium calcium exchanger (NCLX) or via the ER through the calcium-dependent activation of ER ryanodine receptors (RyRs) contribute to increases in cytosolic Ca2+. RyRs amplify calcium increases originating either intracellularly or at the plasma membrane. RyRs transduce pain signals by amplifying presynaptic calcium increases, leading to neurotransmitter release (W. Huang, Wang, Galligan, & Wang, 2008; Ouyang et al., 2005). Moreover, activating RyR in nociceptors activates α calcium-/calmodulin-dependent protein kinase II (αCaMKII), which primes nociceptors in a calcium- and αCaMKII-dependent manner (Ferrari, Bogen, & Levine, 2013).
Next to calcium sources, calcium sinks and extrusion mechanisms are important regulators of calcium signaling in the nociceptive system and as such may contribute to modulate Ca2+ signaling in pathological pain states. Neuronal calcium sinks include plasma membrane calcium adenosine triphosphatases (ATPases) and NCXs that remove cytosolic calcium. During painful nerve injury, plasma membrane Ca2 + ATPase activity was increased and associated with increased excitability of axotomized sensory neurons (Gemes et al., 2012). During peripheral neuropathic pain, NCX operated in reverse mode, allowing cytosolic Ca2+ entry while pumping out Na+ in sensory neurons (Kuroda et al., 2013; Muthuraman, Jaggi, Singh, & Singh, 2008). Moreover, reduced NCX channel trafficking to the nerve ending at the site of inflammation could explain the increase in the amplitude and duration of depolarization-evoked Ca2 + transients in nociceptive afferents (Scheff & Gold, 2015). In contrast, in paclitaxel-induced (chemotherapy) neuropathy, the duration of the depolarization-evoked Ca2 + transients in the soma of affected neurons was reduced, which was associated with increased NCX activity (Yilmaz & Gold, 2016).
Sarco-/endoplasmic reticulum calcium ATPases (SERCA) pump Ca2 + into the ER, and in various models of neuropathic pain, SERCA function and ER calcium content were reduced in sensory neurons (Duncan et al., 2013; Gemes et al., 2009; Y. Guo et al., 2017; Rigaud et al., 2009).
The uptake of calcium ions by mitochondria is controlled by mitochondrial uniporter (MCU). Calcium uptake and release by mitochondria has been proposed to control the duration of neurotransmitter release from sensory fibers, and it has been identified as a primary regulator of presynaptic calcium transients (H. Y. Kim et al., 2011; Medvedeva, Kim, & Usachev, 2008; Shutov, Kim, Houlihan, Medvedeva, & Usachev, 2013). Neuropathy-inducing chemotherapeutics reduce calcium buffering capacity and calcium release from mitochondria (Canta, Pozzi, & Carozzi, 2015; Flatters, 2015). Moreover, mitochondria are functionally coupled to TRPVs by providing prolonged presynaptic Ca2 + signaling and glutamate release after TRPV1 activation, and they contribute to enhanced neuronal firing and neurotransmitter release (Dedov & Roufogalis, 2000; Medvedeva et al., 2008).
Various calcium-binding proteins that buffer calcium, such as the signaling molecule calmodulin, provide a way to control calcium signaling in sensory neurons and contribute to chronic pain. For example, N-terminal EF-hand Ca2+-binding protein 2 (NECAB2), a Ca2+-binding protein, facilitates inflammatory pain hypersensitivity (M. D. Zhang et al., 2018). Calmodulin has differential regulatory effects on the sensitivity of VGCCs through binding to the calmodulin-binding domain of the channel to regulate Ca2+ homeostasis (Nejatbakhsh & Feng, 2011). CaMKII is a serine/threonine kinase that is activated when Ca2+/calmodulin binds. CaMKII is mainly expressed in the spinal dorsal horn and in sensory neurons of the DRG, and its expression is increased during chronic pain states (Y. Chen, Luo, Yang, Kirkmire, & Wang, 2009; Dai et al., 2005; Hasegawa, Kohro, Tsuda, & Inoue, 2009; Luo et al., 2008). Inhibiting CaMKII activity reversed inflammatory and neuropathic pain (Y. Chen et al., 2009; Dai et al., 2005; Garry et al., 2003; Hasegawa et al., 2009; Luo et al., 2008). CaMKII phosphorylates ionotropic glutamate receptors, such as the N-methyl-d-aspartate (NMDA) receptor, enhancing its function, promoting influx of Ca2+, and initiating a feed-forward loop between an increase in Ca2+, CaMKII, and NMDA receptor activity; neuronal plasticity; and maintenance of chronic pain (Figure 3) (Hagenston & Simonetti, 2014).
Mitogen-Activated Protein Kinase
Inflammatory stimuli or nerve damage activate MAPKs), such as p38, extracellular signal–regulated kinases (ERK), and c-Jun N-terminal kinase (JNK), through different upstream MAPK kinases, which in their turn are activated by MAPK kinase kinases. Activated MAPKs phosphorylate downstream molecules (e.g., enzymes and transcription factors) at serine or threonine residues and contribute to the sensitization of sensory neurons in inflammatory and neuropathic pain conditions (Figure 3). Beyond their role in sensory neurons, clear evidence exists that several MAPKs are activated in nonneuronal cells, such as glia, and contribute to pathological pain. The majority of data on the role of these MAPKs were obtained with the use of specific inhibitors in vivo. A limitation of this experimental approach is that it does not allow to discriminate the cell-specific role of MAPKs in the regulation of inflammatory and neuropathic pain. In general, what is learned from these studies is that MAPK inhibitors are able to inhibit inflammatory and neuropathic pain, but do not affect basal pain thresholds. These studies indicated that the MAPKs regulate pathological pain states but did not provide tonic signals for tuning the threshold of physiological pain detection (Kasuya, Umezawa, & Hatano, 2018; Ma & Quirion, 2005; Manassero et al., 2012).
The p38 MAPK family is a central transducer of cellular stress pathways and consists of four isoforms (α, β, γ, δ), with p38α and β most prominently expressed in the nervous system. The isoform p38α MAPK is mainly expressed in neurons; p38β MAPK is mainly expressed in spinal microglia (Fitzsimmons et al., 2010; Svensson et al., 2005). Extracellular signaling molecules, such as not only cytokines and growth factors but also bacterial products, oxidative stress, hypoxic and osmotic insults, and others, are activators of p38 MAPK through activating upstream kinases, such as mitogen-activated protein kinase kinase (MKK)3 and MKK6. p38 MAPK further relies on signal propagation through direct activation of numerous downstream kinases, including members of the MAPK-activated protein kinase (MAPKAP) family, mitogen- and stress-activated kinase (MSK) and MAPK-interacting kinase (MNK) kinases (Cuenda & Rousseau, 2007; Kasuya et al., 2018). In addition, phosphorylated p38 MAPK (p-p38 MAPK) translocated to the nucleus and phosphorylated various transcription factors, including cAMP response element-binding protein (CREB) and activating transcription factor 2 (ATF-2) (Y. Yang et al., 2014).
In various animal models of inflammatory and neuropathic pain, activation of p38 MAPKs was observed in sensory neurons. For example, p-p38 MAPK was increased in DRG sensory neurons after a plantar incision. Hind paw inflammation increased p-p38 in C fibers, starting within 24 hr, and was maintained for 7 days. In this model of CFA-induced inflammatory pain, p38 activation was downstream of NGF, and p38 activation increased TRPV1 levels in nociceptor peripheral terminals in a transcription-independent fashion, which contributed to the maintenance of inflammatory heat hypersensitivity (Ji, Samad, Jin, Schmoll, & Woolf, 2002; Mizukoshi et al., 2013). In addition to the NGF, inflammatory mediators activated p38 MAPK-dependent pathways in sensory neurons to enhance the excitability of sensory neurons (Binshtok et al., 2008; Hudmon et al., 2008). The pro-inflammatory cytokine IL-1β increased phosphorylation of p38 MAPK in sensory neurons in vitro and in cutaneous sensory fibers in vivo. IL1β-induced p38 activation in sensory neurons enhanced TTX-resistant sodium currents and induced mechanical and thermal hypersensitivity, which were blocked by the p38 MAPK inhibitor SB203580 (Binshtok et al., 2008). During CFA-induced inflammatory pain, p38 increased Nav1.8 current density in sensory neurons through phosphorylation of two serine residues of the Nav1.8, without altering activation or steady-state inactivation properties of the channel (Hudmon et al., 2008). Thus, activation of p38 MAPK sensitized neurons through various transcriptional-independent mechanisms during inflammatory pain.
In models of neuropathic pain, increased p38 activity was also observed; it was maintained for weeks after spinal nerve ligation (SNL) or in a transgenic mouse model of diabetes-induced neuropathy (Cheng et al., 2010; S. X. Jin, Zhuang, Woolf, & Ji, 2003). Intrathecal injections with a p38 MAPK inhibitor reversed nerve injury–induced hypersensitivity, but there is still debate on how p38 MAPK regulates neuronal functioning during neuropathic pain (S. X. Jin et al., 2003; Qu et al., 2016; Sorge et al., 2015; Taves et al., 2016; Tsuda, Mizokoshi, Shigemoto-Mogami, Koizumi, & Inoue, 2004). Possibly, p38 MAPK signal propagation promotes excitability and ectopic discharges in sensory neurons in neuropathic pain by increasing Nav1.8 sodium channel current density (Hudmon et al., 2008) or increasing TRP channel expression, such as TRPV1, TRPA1, and TRPV4 expression (Obata et al., 2006; Qu et al., 2016). Another possible role of p38 MAPK in the development of neuropathic pain is through modulating mitochondria that play a central role in neuronal signaling and in the development of neuropathic pain (Flatters, 2015). Mitochondrial motility is regulated by p38 MAPK because active p38α MAPK inhibits axonal transport, including that of mitochondria (L. Li et al., 2015; Morfini et al., 2013). Moreover, reactive oxygen species produced during neuropathic pain (Duggett et al., 2016) inhibited mitochondrial motility in a fashion dependent on p38α MAPK activity (Debattisti, Gerencser, Saotome, Das, & Hajnoczky, 2017).
Despite the role of p38 MAPK in sensory neurons in pathological pain, most data point to a role of p38 activation in microglia. During inflammatory and neuropathic pain, the majority of phosphorylated p38 is observed in microglia in laminae I–IV of the dorsal horn of the spinal cord (J. Cao, Wang, Ren, & Zang, 2015; S. Y. Kim et al., 2002; Svensson et al., 2003; Tsuda et al., 2004). Knockdown of specific p38 MAPK isoforms in the spinal cord indicated that the isoform present in microglia (p38β, but not the neuronal p38α MAPK) prevented the development of substance P–induced hyperalgesia, supporting the role of p38 MAPK pathway in microglia (Svensson et al., 2005). Many other studies showed that activation of p38 MAPK in microglia was important for the development of inflammatory and neuropathic pain. However, others have claimed that spinal p38 MAPK inhibition was only effective to treat neuropathic and inflammatory pain in males and not in females, suggesting that spinal p38 signaling is sex dependent (Taves et al., 2016). Mechanistically, activation of p38 MAPK in microglia regulates pain through inducing the expression of various genes, including pro-inflammatory cytokines (e.g., COX, TNF, IL-1β, and IL-6), that can sensitize neurons and induce pain (Ji & Suter, 2007; Y. L. Liu et al., 2007; Mizukoshi et al., 2013).
Based on preclinical studies, inhibition of p38 MAPK has been suggested as a potential therapeutic avenue to treat chronic pain. However, so far human trials using p38 MAPK inhibitors have been rather disappointing because of low efficacy of these inhibitors in inhibiting inflammation and pain and because of the observed toxicities (Clark & Dean, 2012; Hammaker & Firestein, 2010; Ostenfeld et al., 2015). One reason for therapeutic failure could be that all first- and second-generation p38 MAPK inhibitors were designed to target the ATP-binding pocket of p38 MAPK, a common domain found in multiple kinases, likely affecting other signaling kinases as well, thus limiting their efficacy. Despite current disappointing results, novel strategies are being explored to target p38 MAPK more selectively to treat pathological pain. For example, more selective novel compounds are being developed by targeting the docking groove of p38 MAPK, instead of the catalytic site, in order to reduce binding of upstream kinases and downstream targets (Shah et al., 2017; Willemen et al., 2014). Those inhibitors exert anti-inflammatory effects and inhibit inflammatory pain in rodent models, but clinical benefits still need to be investigated.
Extracellular Signal–Regulated Kinases
The ERK family consists of several isoforms, with ERK1 and ERK2 the most well-known isoforms. Both isoforms are activated through dual phosphorylation of threonine and tyrosine residues by MKKs (MEK1/2), which are activated by the small guanine triphosphatase (GTPase) Ras and Ras-activated kinases (Raf) (Ma & Quirion, 2005). Inactivation of ERK needs removal of one or both phosphorylated sites by phosphatases, which are important to regulate temporal ERK activity in a large variety of cellular processes (Busca, Pouyssegur, & Lenormand, 2016). ERK signal propagation was originally identified as a primary effector of growth factor receptor signaling. However, ERK signaling cascades are also triggered by persistent neural activity and pathological stimuli. For example, cytosolic Ca2+ fluxes induced by neuronal activity triggered the GTPase Ras to activate MEK/ERK signal propagation (Cruz & Cruz, 2007; Thomas & Huganir, 2004). A growing body of evidence demonstrates an involvement of ERK in neuronal plasticity in pain hypersensitivity (Ji, Gereau, Malcangio, & Strichartz, 2009). The phosphorylation of ERKs under different persistent pain conditions induces and maintains pain hypersensitivity via nontranscriptional and transcriptional regulation (Figure 3). Because the majority of studies indicated a role of stimulus-induced ERK activation in spinal neurons and, to a more limited extent, in primary sensory neurons, we also discuss the role of ERK signaling in spinal cord neurons.
Activation of C-fiber nociceptors (capsaicin, heat) induced ERK phosphorylation (p-ERK) in dorsal horn spinal cord neurons very rapidly (<1 min) and was intensity and duration dependent; the number of pERK–positive neurons increased with stronger stimuli, and very short noxious stimuli were not able to induce p-ERK (Wei et al., 2006). This spinal neuron p-ERK was only induced by noxious stimuli and not by innocuous stimuli (Ji, Baba, Brenner, & Woolf, 1999). pERk was also induced after intense and persistent noxious input produced by formalin, NGF, nerve injury, and inflammation. Similarly, in these cases ERK was also rapidly phosphorylated (within minutes) in primary afferent neurons, spinal dorsal horn neurons, peripheral nerve fibers, and nerve terminals in the skin (Dai et al., 2002; Ji et al., 1999; Ma & Quirion., 2005; O’Brien et al., 2015; Obata, Yamanaka, Dai, et al., 2004; Obata et al., 2003; Singh & Vinayak, 2017; X. S. Song et al., 2005). Various studies from different laboratories have shown that glutamate transmission via NMDA receptors is essential for ERK activation in spinal cord neurons (Ji et al., 1999; Lever, Pezet, McMahon, & Malcangio, 2003; Wei et al., 2006). The population of primary afferent neurons in which p-ERK is activated after inflammation or nerve injury is different. Inflammation, as well as heat, induced p-ERK in small-to-medium size tropomyosin receptor kinase A (TrkA) or TRPV1 positive DRG neurons; after nerve injury, phosphorylated ERK was mainly observed in medium-to-large size neurons (Obata, Yamanaka, Dai, et al., 2004; Obata et al., 2003). Intriguingly, in injury or inflammatory conditions, ERK was also activated by sensory stimuli that in healthy condition do not activate ERK. In those injury or inflammatory conditions, low-threshold electrical stimulation (H. Wang et al., 2004) and tactile stimulation (Hao et al., 2005) was sufficient to induce ERK activation in spinal cord neurons. Similarly, movement of the inflamed joint but not of the noninflamed joint increased p-ERK in spinal cord neurons (Cruz, Neto, Castro-Lopes, McMahon, & Cruz, 2005). Thus, stimulus-induced ERK activation may play an important role in the development of tactile allodynia or movement-induced pain in chronic pain.
The contribution of stimulus-induced ERK activation in pain is highlighted by the fact that pharmacological or genetic inhibition of ERK1/2 prevented the central sensitization-mediated second phase of the formalin test and capsaicin-induced secondary mechanical hypersensitivity (Ji et al., 1999; Karim, Hu, Adwanikar, Kaplan, & Gereau., 2006; Karim, Wang, & Gereau, 2001; Y. Kawasaki et al., 2004; Torebjork, Lundberg, & LaMotte, 1992). Moreover, inhibition of ERK1/2, in particular of ERK2, prevented inflammatory hyperalgesia and allodynia following hind paw injection of CFA or after joint monoarthritis or inflammatory visceral pain (Alter, Zhao, Karim, Landreth, & Gereau, 2010; Cruz et al., 2005; Galan, Cervero, & Laird, 2003; Ji, Befort, Brenner, & Woolfe, 2002; Y. Kawasaki et al., 2004; Obata et al., 2003). Abrogation of ERK2 expression in nestin-positive cells (neurons and astrocytes) impaired development of nerve injury–induced mechanical hypersensitivity (Otsubo et al., 2012).
The functional effects of stimulus-induced ERK activation in spinal neurons include post-translational regulation that is likely sufficient to induce central sensitization; transcriptional regulation is important to maintain central sensitization. ERK-dependent post-translational regulation includes potentiation of glutamatergic synaptic transmission by enhancing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA currents (Kohno et al., 2008; Y. Qin et al., 2005; Slack, Pezet, McMahon, Thompson, & Malcangio, 2004).
Moreover, ERK activation led to increases in excitability of spinal superficial dorsal horn neurons (Hu & Gereau, 2003), which was mediated by a reduction in transient outward (A-type) potassium currents largely carried by Kv4.2 channels. Finally, ERK1/2 activation was observed after spinal LTP, a form of spinal memory thought to contribute to chronic pain (Ji et al., 2009; Malcangio & Lessmann, 2003; Sandkuhler, 2000), and inhibition of MEK/ERK before or after LTP-inducing stimuli blocked this spinal LTP (Xin et al., 2006). ERK-mediated transcriptional changes were induced through translocation of ERK to the nucleus and phosphorylation of various transcription factors, including CREB. ERK-mediated CREB phosphorylation initiated expression of downstream targets, including several “pain genes” that are involved in central sensitization (e.g., brain-derived neurotrophic factor [BDNF], neurokinin 1 [NK1], c-Fos, CGRP) (Crown et al., 2006; Ji, Befort, et al., 2002; Y. Kawasaki et al., 2004), and suggest long-lasting neuronal plasticity induced by ERK1/2.
Although the majority of studies point to ERK activation in the dorsal horn of the spinal cord, ERK is also activated in primary afferents, as mentioned previously. Some studies have shown ERK-dependent regulation of primary sensory neurons in neuropathic or inflammatory pain models. In models of neuropathic pain, including chronic constriction injury (CCI), spared nerve injury (SNI), or SNL, p-ERK levels were increased for long periods (>7 days) in medium-to-large size neurons of the DRG. Suppression of ERK1/2 pharmacologically with intrathecal U0126 (MEK inhibitor) inhibited mechanical hypersensitivity (Melemedjian et al., 2011; Obata et al., 2003; Obata, Yamanaka, Kobayashi, et al., 2004). Moreover, hyperalgesia caused by injection of CFA in the hind paw or in the L4/L5 root (to induce local inflammation at the DRG) was dependent on NGF-induced ERK signaling in small-to-medium size TrkA+ DRG neurons, which induced BDNF expression (Obata, Yamanaka, Dai, et al., 2004; Obata et al., 2003). ERK signaling in sensory neurons can potentially contribute to hyperexcitability because ERK can phosphorylate Nav1.7, a channel associated with human pain conditions, on specific residues of an intercellular loop of Nav1.7, leading to changes in gating properties that enhanced action potential firing (Stamboulian et al., 2010).
Although these studies mainly relied on MEK inhibitors that also could have inhibited dorsal horn–activated ERK1/2, (conditional) knockout mice have aided in identifying specific roles of ERK1 and 2 in primary sensory neurons. Global ERK1 deletion did not affect acute and chronic inflammatory or neuropathic pain, suggesting that ERK1 is not required for nociceptive sensitization (Alter et al., 2010). Abrogation of ERK2 in spinal neurons (and astrocytes), using nestin promoter-driven CRE transgenic mice, impaired development of nerve injury–induced mechanical hypersensitivity but not thermal hypersensitivity (Otsubo et al., 2012), indicating that most likely spinal ERK2 is required for neuropathic pain. In contrast, ERK2 signaling in both spinal and primary afferent neurons contributed to inflammatory pain. Cell-specific deletion of ERK2 in inflammatory conditions in spinal neurons using neurotropic adenoassociated viral vectors expressing ERK2 small interfering RNA and ERK2 deletion in primary afferent using conditional Nav1.8+ nociceptor-specific ERK2 knockout mice, both protected mice against the development of CFA-induced inflammatory pain (O’Brien et al., 2015; Xu, Garraway, Weyerbacher, Shin, & Inturrisi, 2008).
Another member of the ERK family, ERK5, is activated by MEK5 (G. Zhou, Bao, & Dixon, 1995), and MEK5 is activated by MEKK2/3 (Nishimoto & Nishida, 2006). Although the molecular weight of ERK5 (115 kDa) is quite different from ERK1/2, it shares high homology in the amino-terminal kinase domain with ERK1/2 and contains the Thr-Glu-Tyr (TEY) motif in the activation loop, similar to ERK1/2. After peripheral nerve injury, ERK5 is phosphorylated in spinal microglia and small-to-medium size DRG neurons (Obata et al., 2007; J. L. Sun et al., 2013). Knockdown of ERK5 with intrathecal antisense oligodeoxynucleotides injections prevented nerve injury–induced hypersensitivity associated with reduced spinal microglia activation and downregulation of TRPV1, TRPA1, and BDNF expression in sensory neurons (Obata et al., 2007; J. L. Sun et al., 2013). Thus, some evidence points toward a role of ERK5 in spinal microglia and sensory neurons.
c-Jun N-Terminal Kinase
The JNK family consists of the three isoforms: JNK1, JNK2, and JNK3. JNK activation requires dual phosphorylation of threonine and tyrosine residues by the MAPK kinases MKK4 and MKK7. These MKKs are activated by MKKKs (e.g., Apoptosis signal-regulating kinase 1 [ASK1], MEKK1, MEKK4) in response to various triggers, including pro-inflammatory cytokines, a rise in cytosolic Ca2+, and reactive oxygen species (ROS) (Bonny, Borsello, & Zine, 2005; Gao & Ji, 2008). JNK1 and 2 are ubiquitously expressed; JNK3 is primarily expressed in heart, pancreas, and the nervous system (Manassero et al., 2012). More than 50 substrates for JNKs have been identified, including receptors and transcription factors, with c-Jun the best known JNK substrate. JNK signal transduction contributes to the onset and the maintenance of neuropathic pain via distinct mechanisms in sensory neurons and spinal cord. Following nerve injury, JNK was rapidly activated by phosphorylation, and its expression in neurons remained elevated for weeks, until the neuron died or until its axon regenerated (Herdegen & Waetzig, 2001; Kenney & Kocsis, 1998; Zhuang et al., 2006). Persistent JNK activation, in particular of the isoform JNK1, was also observed in activated spinal astrocytes in chronic inflammatory and neuropathic pain models (Gao et al., 2010; Zhuang et al., 2006).
Activation of JNK has been associated with an increase in c-Jun expression, an event upstream of production of neurosensitizing substances (e.g., BDNF, IL-1β, TNF, PGE2) by spinal glia (Gao et al., 2009, 2010; Sanna & Galeotti, 2018). JNK activation was also observed in small-to-medium size DRG neurons in models of neuropathic pain (SNL, SNI, diabetic neuropathy) and inflammatory pain (CFA) (Doya et al., 2005; Kenney & Kocsis, 1998; Lindwall, Dahlin, Lundborg, & Kanje, 2004; Middlemas, Agthong, & Tomlinson, 2006; Obata, Yamanaka, Kobayashi, et al., 2004; Zhuang et al., 2006). Activated JNK induced upregulation of c-Jun in the nucleus of DRG neurons after nerve injury, which was suppressed by the JNK inhibitor D-JNKI-1 (Kenney & Kocsis, 1998; Manassero et al., 2012; Zhuang et al., 2006). Inhibition of all JNK isoforms with D-JNKI-1 suppressed nerve injury-, capsaicin-, and CFA-induced hypersensitivity, indicating a role for JNK/c-Jun signaling in neuropathic and inflammatory pain (Gao & Ji, 2008; Gao et al., 2010; Manassero et al., 2012; Zhuang et al., 2006). The precise mechanisms as to how JNK contributes to maladaptive changes in sensory neurons during neuropathic pain remains unclear. Nevertheless, in general it is thought that JNK activation causes transcriptional changes that are primarily aimed at restoring disrupted connections and recovering function after nerve damage. Indeed, c-jun regulated target genes involved in axonal outgrowth in sensory neurons (Kenney & Kocsis, 1998). JNK inhibition during neuropathic pain prevented the upregulation of growth associated protein 43 (GAP43), a marker of neurite growth or sprouting, while pain was inhibited (Manassero et al., 2012).
To distinguish which JNK isoform is important for pain signaling, studies were performed in JNK isoform-specific knockout mice. CFA-induced hypersensitivity was attenuated in mice lacking JNK1; mice lacking JNK2 did develop inflammatory pain to the same extent as wild-type mice (Gao et al., 2010). In contrast, development of peripheral nerve injury–induced neuropathic pain was prevented by inhibition of all JNK isoforms with D-JNKI-1, but the onset of neuropathic pain was not affected in knockout mice for each individual JNK isoform (Manassero et al., 2012). Thus, all JNK isoforms contributed to maintain neuropathy, while JNK1 was mainly important for maintaining inflammatory pain. Whether these roles of the JNK isoforms are specific for sensory neurons remains elusive because previous studies used constitutional knockout mice. Similarly, the downstream targets of JNK/c-Jun/AP-1 involved in regulating sensory neuron activity remain to be investigated.
Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that phosphorylate the D-3 position of phosphatidylinositol lipids to produce Phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3), acting as a membrane-embedded second messenger to activate downstream signaling molecules (e.g., Akt/Protein kinase B [PKB], ERK, mammalian target of rapamycin [mTOR]), with Akt postulated to mediate most downstream effects (Hawkins & Stephens, 2015). PI3Ks are activated by GPCRs, tyrosine kinase receptors, and depolarization-induced Ca2+ concentration elevations (Brennan-Minnella, Shen, El-Benna, & Swanson, 2013). For example, NGF strongly activated PI3K in DRG neurons through binding to the TrkA receptor (W. Zhu & Oxford, 2007; Zhuang, Xu, Clapham, & Ji, 2004). Capsaicin activated PI3K in DRG neurons via increasing intracellular Ca2+ (Zhuang et al., 2004). Moreover, Akt activation downstream of PI3K activity in DRG neurons was activity dependent (Pezet, Spyropoulos, Williams, & McMahon, 2005).
The PI3K family is divided into four classes containing different isoforms, each involved in numerous cellular functions. Class I isoforms (e.g., PI3Kα, β, δ, γ) are most extensively studied and participate in pain signaling. PI3Kα is localized at central terminals of sensory afferent fibers and neurons in the ventral horn of the spinal cord. PI3Kβ is mainly expressed in spinal dorsal horn neurons and DRG neurons; PI3Kγ is mainly detected in a subpopulation of IB4-positive DRG neurons. PI3Kδ is present in spinal cord white matter oligodendrocytes and astrocytes (Leinders et al., 2014). Most data suggest that spinal PI3K signaling is involved in both inflammatory and neuropathic pain. Signs of PI3K activity and activity of its downstream molecules (e.g., Akt) were elevated in the spinal cord during inflammatory and neuropathic pain conditions (J. R. Guo et al., 2017; D. Jin, Yang, Hu, Wang, & Zuo, 2015; Leinders et al., 2014; W. Liu, Lv, & Ren, 2018; R. Q. Sun, Tu, Yan, & Willis, 2006). Intrathecal injection with a broad PI3K inhibitor or inhibitors of downstream molecules of PI3K signaling (e.g., PKB/Akt) prevented or reversed inflammation-, spinal cord injury–, and nerve injury–induced hypersensitivity (Choi, Svensson, Koehrn, Bhuskute, & Sorkin, 2010; Leinders et al., 2014; W. Liu et al., 2018; Pezet et al., 2008; R. Q. Sun et al., 2006; X. Wang, Li, Huang, & Ma, 2016).
Activity of PI3K is required for central sensitization because in vitro and in vivo electrophysiological studies showed that signs of central sensitization and windup (frequency-dependent increase in the excitability of spinal cord neurons) were reduced by PI3K inhibitors (W. Liu et al., 2018; Pezet et al., 2008). For example, PI3K inhibitors prevented AMPA receptor (glutamate receptor) trafficking to plasma membranes of neurons in the spinal cord, limiting sensitization and chronic pain development (Galan, Laird, & Cervero, 2004; Leinders et al., 2014).
The various PI3K isoforms display specificity with regard to neuron subtypes, as well as to specific tissues. Intrathecal injection with an antagonist for isoform PI3Kβ, but not antagonists of other isoforms, blocked inflammation-induced AMPA receptor trafficking and pain (Leinders et al., 2014; Pritchard, Falk, Larsson, Leinders, & Sorkin, 2016). In contrast, intraplantar administration of PI3Kα, β, or γ antagonists during inflammation-induced pain reduced signs of inflammation (e.g., immune cell infiltration); however, only the specific PI3Kγ antagonist prevented the inflammation-induced hypersensitivity and spinal c-Fos expression (Leinders et al., 2014). PI3Kγ is mainly expressed in IB4- and TRPV1-positive DRG neurons (T. M. Cunha et al., 2010; Konig et al., 2010; Leinders et al., 2014). Thus, the PI3Kγ isoform is involved in peripheral nociception, while PI3Kβ mainly enhances central sensitization and persistent pain.
Through various mechanisms, PI3K can contribute to neuronal sensitization. PI3Kγ co-immunoprecipitates with TRPV1 in DRG neurons, and TrkA signaling facilitates trafficking of TRPV1 to the plasma membrane dependent on PI3K activity, suggesting that PI3Kγ is physically and functionally coupled to TRPV1 (A. T. Stein, Ufret-Vincenty, Hua, Santana, & Gordon, 2006). PI3K activation is also associated with trafficking of other ion channels, such as acid-sensing ion channel 1 (ASIC1) and VGCCs (Duan et al., 2012; Viard et al., 2004), and it increases TRPV1 and Nav1.8 current densities through enhancing expression of these channels.
Although the majority of data point to a pro-nociceptive role of PI3K, some evidence exists that PI3K can exert antinociceptive effects. First, PI3K inhibition enhanced and prolonged IL1β and TNF-induced hyperalgesia (Eijkelkamp et al., 2012). Second, a selective PI3Kγ inhibitor or antisense oligodeoxynucleotides against PI3Kγ prevented the antinociceptive effect of morphine (T. M. Cunha et al., 2010).
Mammalian Target of Rapamycin
The mTOR is a serine-threonine kinase belonging to the phosphatidylinositol 3-kinase–related kinase family of protein kinases. mTOR is the core component of the protein complexes mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is regulated by upstream activation of TrKs and engagement of PI3K/AKT signaling. mTORC1 signal propagation involves the interaction of mTOR with the protein raptor to phosphorylate p70 ribosomal S6 protein kinase (p70S6K) and the eukaryotic initiation factor 4E–binding protein 1 (4E-BP1). This eIF4 complex is associated with efficient translation of target messenger RNAs (mRNAs; Sonenberg, 2008). In mTORC2, mTOR interacts with the rapamycin-insensitive companion of mTOR (rictor) and phosphorylates PKB/Akt and PKC proteins (Lisi, Aceto, Navarra, & Dello Russo, 2015). mTOR is a potent regulator of cellular growth and processes such as protein translation, autophagy, and cellular metabolism (Saxton & Sabatini, 2017). mTORC1 activation promotes extensive axon regeneration following traumatic injury in both the peripheral nervous system and the CNS (Abe, Borson, Gambello, Wang, & Cavalli, 2010; Park, Liu, Hu, Kanter, & He, 2010; Park et al., 2008). Importantly, data indicate that mTOR activity is also involved in neuroplasticity in chronic pain (Asiedu, Dussor, & Price, 2016). mTORC1 is ubiquitously expressed; however, some reports suggest that the active form of mTORC1 (phosphorylated) is predominantly observed in A-fiber axons and C-fiber axons in both the skin and the dorsal root (Geranton et al., 2009; Jimenez-Diaz et al., 2008; Obara et al., 2011). Mediators well known to sensitize nociceptors, (e.g., NGF) increased mTORC1 activity in DRG neurons and their peripherally projecting axons (Melemedjian et al., 2010, 2011). Moreover, inflammation or tissue and nerve injury activated mTORC1 in unmyelinated neurons of the DRG and neurons in the superficial dorsal horn of the spinal cord (mainly lamina I/III neurons, some glia cells) (Asante, Wallace, & Dickenson, 2010; Geranton et al., 2009; Izumi, Sasaki, Hashimoto, Sawa, & Amaya, 2015; X. Wang et al., 2016). Similarly, activation of the mTORC1 cascade was observed in the DRG after peripheral inflammation or tissue injury and was inhibited by rapamycin (Izumi et al., 2015; Liang et al., 2013). Local or systemic administration of mTORC1 inhibitor did not alter sensory thresholds in naïve mice or rats. However, local, systemic, or intrathecal administration of mTORC1 inhibitors, such as rapamycin, attenuated mTORC1 signaling and decreased inflammation-, bone cancer–, and nerve injury–induced pain, unequivocally linking mTORC1 to pathological pain (Geranton et al., 2009; Jiang et al., 2016; Jimenez-Diaz et al., 2008; Liang et al., 2013; Obara et al., 2011; Price et al., 2007; S. Wang et al., 2016; W. Zhang et al., 2013).
Electrophysiological studies showed that mTOR inhibition reduced synaptic plasticity and windup of wide dynamic range (WDR) after SNL (Asante et al., 2010), suggesting involvement of central mechanisms. Moreover, intrathecal rapamycin or PI3K attenuated spinal cord injury–induced neuropathic pain by alleviating enhanced substance P and CGRP expression in the dorsal horn of the spinal cord (X. Wang et al., 2016). mTORC1 could contribute to pain hypersensitivity though promoting protein synthesis in primary afferents because mTORC1 signaling is a potent activator of protein translation in sensory axons (Khoutorsky & Price, 2018; Terenzio et al., 2018), and protein synthesis in sensory axons is required for both primary and secondary hyperalgesia (Obara, Geranton, & Hunt, 2012).
Overall, mTORC1 is required for full expression of inflammatory and neuropathic pain (Asiedu et al., 2016; Obara &Hunt, 2014). However, constitutive activation of mTORC1 by deleting its negative regulator tuberous sclerosis complex 2 (Tsc2) in nociceptors did not affect baseline mechanical and cold sensitivity. In contrast, Tsc2-deleted mice exhibited reduced noxious heat sensitivity and decreased injury-induced cold hypersensitivity (Carlin et al., 2018). These contrasting findings may be the results of developmental abnormalities in DRG neuron and reduced target innervation due to the constitutional deletion of Tsc2.
Currently, strong evidence for a role of mTORC2 in regulating pain is lacking. Systemic inhibition of both mTORC1 and mTORC2 with Torin 1, a dual inhibitor that blocks mTORC1 and mTORC2 signaling, appeared to be more effective in blocking nerve injury–induced neuropathic pain compared to only mTORC1 inhibition (Obara et al., 2011), suggesting that mTORC2 may have a role in pain regulation.
Despite promising preclinical studies, rodent and human findings rule out rapamycin as a pain therapeutic. First, prolonged mTORC1 inhibition by longer use of rapamycin caused feedback signaling through p70S6K in DRG neurons, leading to ERK activation and hyperexcitability (Melemedjian et al., 2013). Similarly, rapamycin treatment was anecdotally linked to complex regional pain syndrome, and chronic treatment with rapamycin and other mTOR inhibitors (which are currently under testing in clinical studies for effectiveness as cancer treatment) increased the incidence of pain as a side effect (Asiedu et al., 2016; de Oliveira et al., 2011; Massard, Fizazi, Gross-Goupil, & Escudier, 2010; McCormack et al., 2011). Long-term inhibition of mTORC1 with rapamycin downregulated transcriptional regulators of mitochondrial functions, such as the master regulator of mitochondrial biogenesis, PPARγ co-activator-1α (PGC-1) (Cunningham et al., 2007), which may lead to less mitochondria and thus impaired neuronal functioning.
Adenosine Monophosphate–Activated Protein Kinase
Adenosine monophosphate–activated protein kinase (AMPK) is a widely expressed intracellular energy sensor that monitors and modulates energy expenditure. AMPK is activated by the increased intracellular AMP/ATP ratios that occur when energy is deprived (Carling, 2017). Thus, the main function of AMPK is to promote ATP-generating catabolic pathways while turning off ATP-utilizing anabolic pathways (Hardie, Ross, & Hawley, 2012).
Several studies provided evidence that AMPK activity regulated pain processing. Activation of AMPK was linked to inhibiting pain and interfering with pain-promoting signaling cascades such as mTORC1 and ERK (Asiedu et al., 2016). For example, AMPK activators decreased sensory neuron excitability, potentially by preventing sodium channel phosphorylation by kinases such as ERK or via modulation of translation (Asiedu et al., 2016). Otherwise, AMPK may promote ubiquitin-mediated degradation of ion channels because it increases the ubiquitin ligase activity of neuronal precursor cell expressed developmentally down-regulated protein 4-2 (Nedd4-2; also known as NEDD4 like) (Lang & Foller, 2014). Nedd4-2 interacts with multiple channel types, such as potassium voltage-gated (KCNQ) channels, Chloride channel protein 2 (CIC-2) chloride channels, and voltage-gated Na+ channels (Bongiorno, Schuetz, Poronnik, & Adams, 2011). AMPK can also directly target ion channels to affect excitability. For example, AMPK increased the ATP-sensitive K+ channel (Kir6.2) and Kv2.1 channel activity (Sukhodub et al., 2007; Yoshida et al., 2012), and K+ channel activity is associated with decreased cellular excitability. Moreover, AMPK activation limits TRPA1 activity by reducing the amount of membrane-associated TRPA1, potentially reducing excitability (see Figure 4 for an overview of AMPK signaling in pain) (S. Wang et al., 2018).
The pain inhibitory role of AMPK was further confirmed in rodent models of persistent pain. Knockout mice of AMPKα2, the most prominent AMPK isoform in the CNS, developed more severe inflammatory hyperalgesia (Russe et al., 2013). Enhancing AMPK activity attenuated inflammatory and neuropathic pain (Burton et al., 2017; Mejia, Asiedu, Hitoshi, Dussor, & Price, 2016; Melemedjian et al., 2011; Tillu et al., 2012). Intraperitoneal metformin treatment activated AMPK and increased its expression and reversed neuropathic allodynia (Melemedjian et al., 2011). AMPK activators (e.g., metformin, A769662) suppressed hyperexcitability of NGF-treated cultured sensory neurons and inhibited mTOR/ERK signal propagation (Melemedjian et al., 2011; Tillu et al., 2012). Antinociceptive effects of AMPK activators were also observed in models of postsurgical pain (e.g., incision-evoked pain) and in diabetes-induced neuropathy (Gardiner, Compton, Bennett, Kemp, & Ney, 1990; Mejia et al., 2016; Rambabu, Matsuda, & Katunuma, 1986; Tillu et al., 2012; S. Wang et al., 2018). In a mouse model of diabetic neuropathic pain (db/db mice), AMPK activation with metformin inhibited TRPA1 activity in DRG neurons by decreasing the amount of membrane-associated TRPA1, possibly explaining its analgesic effects (S. Wang et al., 2018). Similar effects of AMPK activation were observed in models of inflammatory pain. Activators of AMPK reduced carrageenan-, IL6-, formalin-, and zymosin-induced hypersensitivity (Gentilli et al., 2001; Russe et al., 2013; Tillu et al., 2012). Conversely, AMPK activation inhibitors provoked hyperalgesia by inducing the formation of NOD-like receptor family pyrin domain–containing 3 (NLRP3) inflammasomes. This AMPK-mediated hyperalgesia did not occur in NLRP3−/− knockout mice (Bullon et al., 2016), suggesting a role of AMPK that extends beyond that in neurons only. In line with these findings, in patients with fibromyalgia, reduced phosphor(p)-AMPK levels were observed, and treatment of patients with fibromyalgia for 1 month with the AMPK activator metformin improved pain outcome for at least 7 months (Bullon et al., 2016). Finally, AMPK activation in the spinal cord led to a reduction in secretion of cytokines by glial cells, and it increased expression of glutamate transporters to restore aberrant nerve injury astrocyte-mediated control of synaptic glutamate levels in the dorsal horn (Maixner, Yan, Gao, Yadav, & Weng, 2015).
Sensory Neuron Signaling and Hyperalgesic Priming
Sensory neurons transmitting nociceptive input show remarkable plasticity in response to inflammation or injury. This plasticity is thought to underlie the development of chronic pain states, including persistent neuropathic and inflammatory pain. For example, short-lived episodes of acute pain, induced by inflammation or injury, can trigger long-term adaptations in the sensory nervous system that render neuronal afferents more excitable and cause long-lasting (chronic) pain responses to subsequent activation, even weeks after the resolution of the first acute pain challenge. This phenomenon is called hyperalgesic priming. It was Levine and his colleagues who in the early 2000s developed hyperalgesic priming models (Aley, Messing, Mochly-Rosen, & Levine, 2000; Reichling & Levine, 2009), which have been adapted and further extended by others (Asiedu et al., 2011; Tillu et al., 2012; H. Wang et al., 2013). These hyperalgesic priming models may be viewed as models for the transition from acute to chronic pain and have important clinical implications in that they have aided in understanding the molecular mechanisms and signaling pathways (Figure 5) involved in chronic pain. Importantly, this phenomenon of hyperalgesic priming is clinically observed in pathological conditions, such as fibromyalgia, repetitive strain injury, complex regional pain syndrome type I, and repeat surgery and occupational repetitive stress disorders, for which earlier episodes of pain, inflammation, or injury likely contribute to the chronic pain states (Reichling & Levine, 2009).
Various inducers of acute pain are able to prime nociceptors, and those inducers include ones that cause acute inflammation (carrageenan, IL6, TNF, skin incision); growth factors (NGF, glial-derived neurotrophic factor [GDNF]); or even the chemotactic factor C-C Motif Chemokine Ligand 2 (CCL2) (Asiedu et al., 2011; Dina, Green & Levine, 2008; Ferrari, Bogen, Reichling, & Levine, 2015; Joseph & Levine, 2010a; Kandasamy & Price, 2015; Melemedjian, Tillu, et al., 2014; Reichling & Levine, 2009). Similarly, opioids can induce hyperalgesic priming (Araldi, Khomula, Ferrari, & Levine, 2018; Joseph, Reichling, & Levine, 2010), potentially explaining one of the adverse effects of opioids: opioid-induced hyperalgesia. Finally, specific activation of signaling molecules, such as PKCε, is sufficient to induce priming of nociceptors (Aley et al., 2000). Intriguingly, by lesioning the IB4+ population of sensory neurons, Levine and coworkers showed that PKCε still induced acute hyperalgesia; however, it failed to induce priming. Thus, IB4+ neurons are important for the induction of PKCε-induced priming.
Although various substances can induce hyperalgesic priming, the priming of nociceptors by inflammatory mediators or growth factors is mainly dependent on protein translation and on changes in signaling pathways that are downstream of the stimuli that lead to chronic pain in primed rodents. Hyperalgesic priming increases mRNA translation locally in the afferent nerves, which normally is dormant (Price & Geranton, 2009). NGF and IL6, both mediators that induce hyperalgesic priming, activate kinases such as mTORC1 and ERK that signal to proteins that bind to the 5′ cap structure of mRNAs and locally increase axonal protein synthesis. Blockade of these kinases, or blockade of downstream eIF4F complex formation that is required for the enhanced protein translation, inhibits priming to subsequent PGE2 exposure (Asiedu et al., 2011; Melemedjian et al., 2010). Similarly, inhibition of protein translation with cordycepin inhibited hyperalgesic priming (Ferrari et al., 2015), and the cytoplasmic polyadenylation element-binding protein (CPEB) translation of mRNAs in the peripheral terminal of the nociceptor contributed to maintenance of the primed state (Bogen, Alessandri-Haber, Chu, Gear, & Levine, 2012; Ferrari, Bogen, Chu, & Levine, 2013).
Other evidence that may point to the contribution of protein translation to hyperalgesic priming is that AMPK activation completely blocked the development of incision-induced hyperalgesic priming (Tillu et al., 2012). AMPK activation inhibited axonal protein synthesis through decreasing ERK and mTORC1 activity; however, AMPK activation also affected pathways independent of protein translation (Melemedjian et al., 2011; Melemedjian, Mejia, Lepow, Zoph, & Price, 2014; Tillu et al., 2012). Overall, these findings suggest a role for local translation in the initiation of hyperalgesic priming of nociceptors.
Changes in protein translation may explain the long-lasting maladaptive change in peripheral nociceptors after priming. However, it does not directly provide an explanation why particular inflammatory agents (e.g., PGE2) in naïve rodents produces acute transient hyperalgesia, while after hyperalgesic priming the same agent induces pain that lasts much longer. Intriguingly, a switch in signaling downstream of cAMP likely explains this difference in function outcome. In naïve rodents, PGE2 induced a short-lasting hyperalgesia dependent on the activation of AC, cAMP, and PKA because inhibitors of AC and PKA reduced PGE2 hyperalgesia. In primed rodents, PGE2-induced hyperalgesia was still dependent on cAMP; however, the long-lasting hyperalgesia that was induced in this situation by PGE2 was not affected by PKA inhibitors but depended on PKCε or MEK/ERK (Dina et al., 2003). Similarly, novel signaling molecules were recruited to PGE2 signaling in the primed state; these molecules included inhibitory G protein (Gi), phospholipase C beta 3 (PLCβ3), and PKCε (Dina, Khasar, Gear, & Levine, 2009; T. Hucho & Levine, 2007; Joseph, Bogen, Alessandri-Haber, & Levine, 2007). An important question is how cAMP signaling switches from a PKA-dependent to a PKCε-dependent process.
Work of several groups has indicated that, in primed animals, the cAMP pathways involve activation of the cAMP sensor Epac1 (Eijkelkamp et al., 2010; T. B. Hucho et al., 2005; H. Wang et al., 2013). Epac can signal to PLC, and PLC activation can lead to PKCε translocation to the plasma membrane, suggesting that Epac is a likely candidate to mediate cAMP to PKCε signaling in the primed state (Grandoch, Roscioni, & Schmidt, 2010; Holz, Kang, Harbeck, Roe, & Chepurny, 2006). Inhibition of Epac1 either genetically or pharmacologically blocked prolonged PGE2 hyperalgesia after carrageenan-, incision-, and GDNF-induced hyperalgesic priming (Matsuda et al., 2017; H. Wang et al., 2013; H. J. Wang et al., 2018). The switch to an Epac1-dependent process in primed rodents may be explained by the finding that a transient episode of inflammation reduced expression of GRK2 in IB4+ neurons. GRK2 binds and phosphorylates Epac1 at Ser-108 in the Disheveled/Egl-10/pleckstrin domain, an event that inhibits agonist-induced translocation of Epac1 to the plasma membrane and downstream Rap1 activation (Singhmar et al., 2016). Reduction of GRK2 in nociceptors using Nav1.8-GRK2+/− mice is already sufficient to mimic hyperalgesic priming (Eijkelkamp et al., 2010). Injection of not only PGE2 but also cAMP analogues induced long-lasting hyperalgesia in Nav1.8-GRK2+/− mice that was independent of PKA, but dependent on PKCε and MEK/ERK, similar to what is observed in primed animals (Eijkelkamp et al., 2010). Overall, these studies indicated that sensory neurons show plasticity in cAMP signaling after a transient inflammation, severely impacting on how these neurons will respond to subsequent inflammatory events.
Conclusion and Final Remarks
A wealth of data indicates that various components of signal transduction pathways in sensory neurons contribute to transient and long-lasting adaptation in neurons to initiate and maintain inflammatory and neuropathic pain. Some of these signal transduction routes may be very specific for inflammatory or neuropathic pain, but activation of various different signaling cascades (PKC, PKA, Epac1, MAPKs, PI3K, etc.) may all lead to a similar outcome: sensitization of sensory neurons. Some important questions remain to be answered. For example, what is the functional consequence when different pathways are simultaneously activated, something that is likely to happen in vivo during inflammatory and neuropathic pain? During inflammation, various inflammatory mediators are produced that each activate different and distinct signal transduction cascades, among them cAMP–PKA, PI3K, and MAPK. Do interactions or crosstalking between these signal pathways occur, and how do they influence each other? It is possible all these pathways modify separate effector molecules through activation of distinct and nonoverlapping signaling components, or some of these signal transduction pathways converge (partially) at a level further downstream. The latter may be exemplified by the fact that ERK activation appears to be downstream of various signal transduction cascades, including cAMP (Isensee, Schild, Schwede, & Hucho, 2017); Epac1 (Eijkelkamp et al., 2010; Monaghan, Mackenzie, Plevin, & Lutz, 2008); PI3K (Zhuang et al., 2004); PKC (Y. Kawasaki et al., 2004); and PKA (Dina et al., 2003; Hu & Gereau, 2003). Moreover, evidence exists that the signaling history of neurons determines how they respond to the same signal later, and that this cellular signal integration can switch sensitizing stimuli into desensitizing stimuli. For example, activation of PKCε induces hyperalgesia. However, when a PKCε activator is applied again, this second application prevents the sensitization via a pathway that is dependent on CaMKII (T. Hucho et al., 2012).
Crosstalk among different signal pathways is of great importance for sensory neurons, in particular with regard to the question of how signaling is involved in resolution of pathological pain. Does the resolution of aberrant pain states require absence of “pro-algetic” signaling cascades, or do “analgesic” intracellular signaling cascades exist? Evidence for inhibition of pain by the AMPK pathway (Asiedu et al., 2016) would indicate the latter, but because AMPK also provides feedback to other pro-algetic pathways (e.g., ERK) (Melemedjian & Khoutorsky, 2015; Price & Inyang, 2015), it would be more likely that these different pathways integrate and converge at some level. Signal integration of analgesic signaling into pro-algetic signaling pathways is exemplified by opioids, which inhibit pro-algetic signaling by inhibiting AC. Lessons might be learned from molecules that can inhibit neuroplastic changes or even return them to naïve conditions. For example, anti-inflammatory cytokines such as IL4 and IL10 or resolvins reduce neuronal hyperexcitability and inhibit pain, in part by directly acting on sensory neurons (Ji, Xu, Strichartz, & Serhan, 2011; Raoof, Willemen, & Eijkelkamp, 2018). These anti-inflammatory cytokines activate the Janus family of tyrosine kinases, also leading to activation of MAPK, such as ERK or p38 MAPK, which are implicated in causing pain. So, why is cytokine-mediated MAPK activation in this case associated with inhibition of pain? It is likely that the downstream effects of MAPK activation on neuronal functioning are context dependent. Indeed, MAPK kinetic profiles can be associated with opposing cellular decisions. For example, p38α MAPK can have pro- and anti-inflammatory roles in macrophages that are context dependent; that is, when IL10 is present, p38 exerts anti-inflammatory effects. Whether similar context dependence exists for MAPK signaling or other signaling cascades in sensory neurons remains to be determined (Fey, Croucher, Kolch, & Kholodenko, 2012; Raza et al., 2017).
Another level of complexity in cellular signaling in pain is that the distinct neuronal subtypes are equipped with specific sets of signaling components that render these cells sensitive to regulation by distinct signal transduction routes. Until now, only very limited knowledge has existed with regard to neuron subtype-specific signaling. Even if the expression of signaling components may not be different between various subtypes, the coupling of these pathways to upstream/downstream pathways may differ between these subsets due to subset specific spatial distribution/cellular compartmentalization. The effect of spatial distribution is highlighted by the fact that lowering GRK2 in IB4+ neurons affects subcellular localization of Epac1, and this affects the ability of Epac1 to activate Rap1 (Singhmar et al., 2016).
In summary, understanding the cellular signal transduction route in pathological pain has provided not only important insights into the pathophysiology of inflammatory and neuropathic pain but also some insights into therapeutic opportunities for the treatment and reversal of chronic pain. Given the large number of receptors and channels involved, targeting more downstream intracellular signal transduction cascades may provide a more effective strategy for pain management than targeting a single receptor or ion channel. However, the broad and wide involvement of these signal transduction pathways in various cellular functions in physiology and pathophysiology may limit their therapeutic potential.
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