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date: 02 June 2020

Voltage-Gated Calcium Channels: Molecular Targets for Treating Chronic Pain

Abstract and Keywords

Voltage-gated calcium channels are important contributors to the transmission and processing of nociceptive information in the primary afferent pain pathway. Several types of calcium channels and their ancillary subunits are dysregulated in response to nerve injury or inflammation. Notably, calcium channels have emerged as prominent targets for analgesics. This chapter discusses the roles of specific types of voltage-gated calcium channels in the afferent pain pathway and their utility as pharmacological targets for therapeutic intervention in chronic pain. Several calcium channel subtypes are dysregulated during chronic pain conditions, giving rise to increased neuronal excitability and synaptic transmission. N-type calcium channels, Cav3.2 T-type calcium channels, and the Cavα2δ subunit are validated targets for the development and clinical use of small organic analgesics, with R-type channels showing potential as possible targets based on preclinical studies.

Keywords: N-type channel, T-type channel, gabapentin, pregabalin, morphine, Cavα2δ

Calcium Channel Subtypes and Structure

Voltage-gated calcium channels are the principal source of depolarization-induced calcium entry into electrically excitable cells (Zamponi, Striessnig, Koschak, & Dolphin, 2015). Calcium influx via these channels governs a wide range of physiological processes, including excitability, calcium-dependent gene transcription, activation of enzymes, and the release of neurotransmitters from presynaptic nerve terminals (Bannister & Beam, 2013; Catterall, Leal, & Nanou, 2013; Simms & Zamponi, 2014; Wheeler et al., 2012). The vertebrate nervous system expresses nine distinct types of voltage-gated calcium channels that are clustered into three major families: Cav1, Cav2, and Cav3. The first two belong to the superfamily of high-voltage–activated (HVA) calcium channels that require large membrane depolarizations to open (for review, see Zamponi et al., 2015). The Cav3 channels are low-voltage–activated (LVA) calcium channels able to open in response to smaller depolarizations (Perez-Reyes, 2003). Cav1 channels support L-type currents in both nerve and muscle and contain four different members: Cav1.1 (skeletal muscle specific), Cav1.2, Cav1.3, and Cav1.4 (Koschak et al., 2003; Mikami et al., 1989; Snutch, Leonard, Gilbert, Lester, & Davidson, 1990; T. Tanabe et al., 1987; Tomlinson et al., 1993; Williams et al., 1992). The Cav2 family includes three members, Cav2.1, Cav2.2, and Cav2.3, which carry, respectively, to P/Q-type, N-type, and R-type calcium currents (Dubel et al., 1992; Mori et al., 1991; Starr, Prystay, & Snutch, 1991; Soong et al., 1993). The three members of the Cav3 family (Cav3.1, Cav3.2, and Cav3.3) all give rise to T-type calcium currents (Cribbs et al., 1998; J. H. Lee, Gomora, Cribbs, & Perez-Reyes, 1999; Perez-Reyes et al., 1998; Snutch & Baillie, 1997a, 1997b). At the molecular and biochemical levels, neuronal HVA calcium channels are heteromultimers comprising principally Cavα1, Cavβ, and Cavα2δ subunits (H. Liu et al., 1996; Takahashi, Seagar, Jones, Reber, & Catterall, 1987; T. Tanabe et al., 1987; Witcher et al., 1993; for review, see Catterall, Perez-Reyes, Snutch, & Striessnig, 2005). These coassemble in a 1:1:1 stoichiometry into a functional calcium channel complex, recently elegantly visualized through cryogenic electron microscopy of an L-type calcium channel complex (J. Wu et al., 2016).

The Cavα1 subunit is the main pore-forming unit and is capable of producing calcium currents even in the absence of ancillary subunits. It features four structural domains, each containing six transmembrane helices plus a pore-forming p-loop motif, along with cytoplasmic N and C termini and large cytoplasmic linkers between domains (Catterall et al., 2005; Zamponi et al., 2015). There are four different genes encoding each of the Cavα2δ and Cavβ subunits. The former is translated from a single gene and proteolytically cleaved into α2 and δ fragments. These are then relinked via disulfide bonds and attached via a Glycosylphosphatidylinositol (GPI) anchor to the extracellular leaf of the plasma membrane (Davies et al., 2010). Its principal functions appear to be to help traffic channel complexes to the plasma membrane, slow the rate of channel internalization, and modulate certain channel biophysical properties (Barclay et al., 2001; Brodbeck et al., 2002; Cantí et al., 2005; Gurnett, De Waard, & Campbell, 1996; Gurnett, Felix, & Campbell, 1997; Klugbauer, Marais, & Hofmann, 2003; Qin, Olcese, Stefani, & Birnbaumer, 1998; Tuluc, Kern, Obermair, & Flucher, 2007; Wakamori, Mikala, & Mori, 1999; Yasuda et al., 2004). The Cavβ subunits are cytoplasmic proteins that interact with the Cavα1 subunit at the cytoplasmic region linking domains I and II (Pragnell et al., 1994). Their functions include refining biophysical properties of the channels along with protection of channels from ubiquitination or proteasomal-mediated degradation (Altier et al., 2011; Buraei & Yang, 2010; Page, Rothwell, & Dolphin, 2016; Waithe, Ferron, Page, Chaggar, & Dolphin, 2011). The ability of the various HVA Cavα1 subunits to interact with different types of Cavβ and Cavα2δ subunits greatly increases the functional diversity of calcium channels beyond the 10 different Cavα1 subunit genes. Functional and modulatory diversity is further enhanced by alternative splicing (for review, see Lipscombe, Andrade, & Allen, 2013; Zamponi et al., 2015) and messenger RNA (mRNA) editing (Huang et al., 2012) of the various calcium channel subunits and through the subtype-specific association with regulatory elements, such as calmodulin and synaptic release proteins (M. G. Kang & Campbell, 2003). Altogether, these factors give rise to a wide spectrum of HVA calcium currents in native tissues. In contrast with HVA channels, Cav3 channels appear to only comprise a Cavα1 subunit; however, they also are subject to considerable alternative splicing (Chemin, Monteil, Bourinet, Nargeot, & Lory., 2001; Swayne & Bourinet, 2008).

Each of the different types of calcium channels exhibits distinct biophysical properties, unique pharmacological profiles, and specific cellular and subcellular expression patterns that correspond to particular physiological roles. For examples, Cav2.2 and Cav2.1 calcium channels are expressed at presynaptic nerve termini, where they control the release of neurotransmitters (Westenbroek et al., 1992, 1995), whereas Cav3 channels tend to be expressed at dendritic sites and cell bodies, where they contribute to neuronal excitability (McKay et al., 2006).

Pharmacological properties have long been used as a means to profile different types of calcium currents. Cav2.2 channels are blocked selectively by ω-conotoxins GVIA and MVIIA, P/Q-type channels by ω-agatoxin IVA, Cav2.3 channels by SNX-482, and L-type calcium channels by a wide range of dihydropyridines (DHPs). Not all DHPs are selective for L-type channels (for a comprehensive review of calcium channel pharmacology, see Zamponi et al., 2015). T-type channels can be inhibited by nickel ions, although these also block R-type channels (Zamponi, Bourinet, & Snutch, 1996). Hence, while pharmacological approaches are a convenient means of typing calcium currents in native cells, these tools have to be applied cautiously and are best combined with biophysical analyses and genetic manipulations.

Calcium Channels Within the Pain Matrix

Calcium channels play multiple critical roles in the transmission and processing of pain-related information within both the primary afferent pain pathway and in the brain (Bourinet et al., 2014; Waxmann & Zamponi, 2014) (Figure 1). In part, the excitability of primary afferent fibers is regulated by T-type calcium channels due to their ability to support rebound bursting (Coulter, Huguenard, & Prince, 1989; Huguenard & Prince, 1992; McCormick & Huguenard, 1992). It is also likely that T-type channels regulate the firing properties of interneurons in the spinal dorsal horn, and they further appear to contribute to neurotransmission at dorsal horn synapses (García-Caballero et al., 2014; Jacus, Uebele, Renger, & Todorovic, 2012) (Figure 1). Among the three members of the T-type calcium channel family, Cav3.2 channels appear to be the most relevant toward nociceptive signaling processes (Snutch & David, 2006). They are expressed in about one third of all dorsal root ganglia (DRG) neurons, with about 30% of those positive for the markers neurofilament protein 200 (NF200) and tropomyosin receptor kinase B (TrkB), indicating that Cav3.2 channels are highly expressed in Aδ-low-threshold mechanoreceptors. About 65% of the Cav3.2-expressing neurons are positive for peripherin, a marker of unmyelinated fibers, a subset of which express the C-fiber low-threshold mechanoreceptor markers, such as TAFA4 and vesicular glutamate transporter 3 (vGLUT3), among others (François et al., 2015). Cav3.2 channels appear to be largely absent in transient receptor potential channel vanilloid 1– (TRPV1)-positive neurons (François et al., 2015). Small interfering RNA– (siRNA)-mediated knockdown experiments (Bourinet et al., 2005; Messinger et al., 2009) and studies on Cav3.2 null mice (Choi et al., 2007) confirmed the importance of these channels for the nociceptive transmission. In addition, redox regulation specific to Cav3.2 T-type channels has been shown to modulate afferent fiber firing and pain responses (J. G. Evans & Todorovic, 2015; Nelson, Joksovic, Perez-Reyes, & Todorovic, 2005; Orestes et al., 2011).

Voltage-Gated Calcium Channels: Molecular Targets for Treating Chronic Pain

Figure 1. Schematic representation of the primary afferent pain pathway. Painful stimuli are detected by nerve endings in the skin, leading to the initiation and propagation of action potentials that then trigger the release of neurotransmitters at synapses embedded in the dorsal horn of the spinal cord. These then activate ascending projections to the brain. Descending modulation of synaptic activity occurs via spinal cord interneurons that are under the control of descending projections from the brain. Key roles of Cav2.2 (N-type) and Cav3.2 (T-type) calcium channels in these processes are indicated.

On the other hand, Cav2.2 N-type calcium channels are the principal mediators of neurotransmitter release at afferent fiber synapses in the dorsal horn (Snutch, 2005). This is supported by observations that intrathecal delivery of specific N-type channel inhibitors mediates potent analgesia (Diaz & Dickenson, 1997; Scott, Wright, & Angus, 2002), and by the fact that mice lacking Cav2.2 channels are hyposensitive to painful stimuli (Hatakeyama et al., 2001; D. S. Kim et al., 2001; Saegusa et al., 2001; Saegusa, Matsuda, & Tanabe, 2002). It is noteworthy that the role of Cav2.2 channels in afferent pain signaling is dependent on Cav2.2 splice isoforms, most specifically concerning alternatively spliced exon 37 (Bell, Thaler, Castiglioni, Helton, & Lipscombe, 2004). It has been shown that nociceptors express two Cav2.2 variants: exon 37a- and exon37b-containing variants (Andrade, Denome, Jiang, Marangoudakis, & Lipscombe, 2010; Bell et al., 2004; Castiglioni et al., 2006; Raingo, Castiglioni, & Lipscombe, 2007). Exon 37a variant channels appear to play a greater role during afferent pain transmission following nerve injury and peripheral inflammation. The two variants differ in their biophysical properties and in their regulation by second messengers (Andrade et al., 2010), supporting the notion that the expression of two different N-type channel isoforms may allow for the fine-tuning of pain signal transmission. There may also be roles for L-type, R-type, and P/Q-type channels in the afferent pain pathway (Fossat et al., 2010; Matthews, Bee, Stephens, & Dickenson, 2007; Radwani et al., 2016), although these are less extensively studied and thus less clearly defined.

Much less is known about the roles of specific calcium channel isoforms in the processing of pain signals in the brain. In the anterior cingulate cortex and insular cortex, two brain structures that are important for pain processing, L-type calcium channels have been suggested to be important for late-phase, long-term potentiation for pain processing (M. G. Liu et al., 2013; Zhuo, 2014); however, these findings were based on pharmacological studies involving the DHP nimodipine, which also blocks T-type calcium channels. Consistent with such a possibility, blocking T-type calcium channels in the anterior cingulate cortex mediates analgesia (Shen et al., 2015). S. J. Kang et al. (2013) demonstrated an important role of N-type calcium channels in excitatory synaptic transmission in this brain region, although how this relates to altered pain behavior remains to be elucidated. Knockout of Cav3.1 channels has been shown to result in increased visceral pain, and this phenomenon has been traced to Cav3.1 channel function in the thalamus (D. Kim et al., 2003). Mutant P/Q-type calcium channels are important players underlying familial hemiplegic migraine type 1 (Brennan & Pietrobon, 2018; Pietrobon & Moskowitz, 2017) and regulate cortical spreading depression linked to migraine aura (van den Maagdenberg et al., 2010). However, it remains to be determined whether they are directly involved in triggering migraine pain. Overall, our current understanding the precise roles of various calcium channels in brain circuits related to pain processing remains scant.

During chronic pain states, numerous types of ion channels have been shown to be dysregulated in the primary afferent pain pathway, including voltage-gated calcium channels and their ancillary subunits. Following peripheral nerve injury and during diabetic neuropathy in animal models, there is an upregulation of Cavα2δ subunits in DRG neurons or spinal cord that is correlated with the development of hyperalgesia (Boroujerdi et al., 2008, 2011; Costigan et al., 2002; C. Y. Li et al., 2001; Luo et al., 2001, 2002; H. Wang et al., 2002; Xiao, Boroujerdi, Bennett, & Luo, 2007). Specific Cavα2δ-1 alternatively spliced variants are expressed in DRG neurons (Angelotti & Hofmann, 1996; Lana et al., 2014), with splice patterns changing following spinal nerve ligation (Lana et al., 2014).

Given the role of Cavα2δ subunits in the trafficking and stability of N-type channels, their upregulation is expected to enhance the expression of HVA calcium channels at presynaptic nerve terminals in the spinal dorsal horn. Indeed, peripheral nerve injury also enhances both R-type and N-type calcium currents in primary afferent neurons, and this upregulation contributes to enhance neurotransmission (Cizkova et al., 2002; J. Yang et al., 2018; L. Yang & Stephens, 2009). This concept is further supported by findings that neurons from transgenic mice overexpressing Cavα2δ-1 exhibit hyperexcitability along with increases in whole-cell calcium currents (C.Y. Li et al., 2006). Similarly, Cav1.2 L-type channels are upregulated following nerve injury (Favereaux et al., 2011), a process apparently mediated indirectly by a change in translational regulation of the microRNA mir-103 that normally suppresses Cav1.2 channel function. Accordingly, mir-103 knockdown results in pain hypersensitivity in rats (Favereaux et al., 2011).

There is a large body of work on the dysregulation of T-type calcium currents in various models of chronic pain. Cav3.2 T-type calcium channels were upregulated in DRG neurons and spinal cord following peripheral nerve injury, in response to both peripheral and visceral inflammation, in a postsurgical pain model (i.e., paw incision), during the development of diabetic neuropathy, and in paclitaxel-induced neuropathy (García-Caballero et al., 2014; Jagodic et al., 2007, 2008; Joksimovic et al., 2018; Y. Li et al., 2017; Marger et al., 2011; Wen et al., 2010). T-type channel upregulation results in enhanced afferent fiber excitability and, in some cases, enhanced synaptic activity in the dorsal horn, both of which are consistent with enhanced sensitivity to peripheral mechanical or thermal stimuli (Todorovic & Jevtovic-Todorovic, 2013). Several mechanisms may underlie the enhanced Cav3.2 channel expression and activity. In the context of diabetes, it has been shown that increasing glucose concentrations in cell culture models resulted in enhanced glycosylation of Cav3.2 channels and increased expression/function of the channels (Orestes et al., 2013; Weiss, Black, Bladen, Chen, & Zamponi, 2013). More broadly, in each of the noted rodent models, there is an upregulation in the expression of the deubiquitinase ubiquitin carboxyl-terminal hydrolase (USP5) (García-Caballero et al., 2014). This enzyme associates with the domain III–IV linker region of Cav3.2 and removes ubiquitin groups from the channel. Consequently, there is increased Cav3.2 protein stability, leading to an accumulation of channels in the plasma membrane along with enhanced synaptic activity and neuronal excitability. Disrupting the association of Cav3.2 with USP5 by short hairpin FNA (shRNA) or interfering peptides protects from neuropathic and inflammatory pain (García-Caballero et al., 2014; Garcia-Caballero, Gadotti, Chen, & Zamponi, 2016). Remarkably, USP5 upregulation can be induced even through noninvasive optogenetic activation of C fibers (Stemkowski et al., 2016). However, these biochemical changes and an associated sensitization to thermal and mechanical stimuli is transient, suggesting that USP5 may, in nonpathological conditions, function as an adaptive and perhaps protective mechanism that goes away under certain circumstances.

Overall, a range of painful conditions across a variety of animal models is associated with increased expression of calcium channel subtypes and auxiliary subunits. It is important to note that similar dysregulation has been reported for many other types of ion channels that contribute to both presynaptic and postsynaptic functions in the afferent pain pathway (Bourinet et al., 2014). This in turn may pose challenges when devising strategies for therapeutic intervention.

Cav2.2 (N-Type) Calcium Channels as Targets for Analgesics

As noted, genetic knockout of Cav2.2 (N type) in mice causes hyposensitivity to inflammatory and neuropathic pain (Hatakeyama et al., 2001; C. Kim et al., 2001; Saegusa et al., 2001), validating Cav2.2 channels as potential targets for analgesics. N-type calcium channels are potently blocked by conotoxins derived from several different types of fish-hunting mollusks, including Conus geographus, Conus magus, Conus fulman and Conus catus (Adams, Smith, Schroeder, Yasuda, & Lewis, 2003; Berecki et al., 2010; S. Lee et al., 2010; Lewis et al., 2000; Motin, Yasuda, Schroeder, Lewis, & Adams, 2007; Olivera, McIntosh, Cruz, Luque, & Gray, 1984; Smith, Cabot, Ross, Robertson, & Lewis, 2002). In many cases, these short 25- to 30-amino acid, highly structured conopeptides are highly selective for N-type calcium channels over other types of voltage-gated calcium channels. Intrathecal delivery of these peptide toxins into rodents mediated analgesia in a range of different pain models (Bowersox & Luther, 1998; Chaplan, Pogrel, & Yaksh, 1994; Scott et al., 2002; Y. X. Wang, Pettus, Gao, Phillips, & Scott Bowersox, 2000), further underscoring the potential utility of peptide blockers as therapeutics.

Indeed, ω-conotoxin MVIIA was developed into a pain therapeutic for intrathecal (i.e., minipump) delivery in patients with cancer pain resistant to classical therapies (Atanassoff et al., 2000; Miljanich, 2004; Thompson, Dunbar, & Laye, 2006; Ver Donck, Collins, Rauck, & Nitescu, 2008; M. S. Wallace et al., 2006). Under the commercial name of Prialt, MVIIA was approved for this purpose by the US Food and Drug Administration (FDA). However, Prialt has a number of side effects, including memory loss, issues with blood pressure control, and unruly behavior, that were unexpected given the mild phenotype of the Cav2.2 null mouse (Penn & Paice, 2000; Rauck, Wallace, Burton, Kapural, & North, 2009; Staats et al., 2004). As a result, Prialt has a very narrow therapeutic window; together with the need for delivery via implanted minipump, its utility is limited.

There have been efforts made to improve on Prialt, such as with ω-conotoxin CVID from Conus catus (Schroeder, Doering, Zamponi, & Lewis, 2006), although these attempts appear to have stalled in phase II clinical trials. Nonetheless, that Prialt can be effective in treating severe pain in humans provides for important target validation, notwithstanding the fact that the origins of the adverse effects remain a mystery. It is possible that this toxin acts on another target besides N-type channels.

A number of pharmaceutical companies have strived to develop high-affinity, selective, small organic blockers of N-type calcium channels for the treatment of pain. Examples of such compounds include peptidylamines, aminopiperidine-sulfonamide, pyrazolpiperidines, cilnidipine, and TROX-1 (Abbadie et al., 2010; Hu, Ryder TR, Rafferty MF, Dooley, et al., 1999; Koganei, Shoji, & Iwata, 2009; Ryder TR, Rafferty MF, Feng, et al., 1999b; Ryder et al., 2000; Swensen et al., 2012), some of which have been tested in rodent pain models. These compounds are typically designed to display state-dependent inhibition of channel activity. Like anticonvulsants and antiarrhythmic drugs (Hille, 1977; Ragsdale, Scheuer, & Catterall, 1991; Willow, Gonoi, & Catterall, 1985), these compounds preferentially target the inactivated state of the channel, giving rise to frequency-dependent inhibition of channel activity. This results in enhanced efficacy of these compounds during conditions wherein pain fibers fire aberrantly, while showing reduced activity during normal neuronal activity. This is also true for several piperazine-derived compounds (Pajouhesh et al., 2010, 2012; Zamponi et al., 2009), including Z160, which showed remarkable oral efficacy across animal models, appeared safe in humans, but subsequently failed two human clinical phase II pain trials. It remains unclear whether the N-type calcium channel in humans is not an appropriate target for drug development, or whether other factors specific to Z160 prevented efficacy in these clinical studies.

There are also indirect means of modulating N-type calcium activity through G protein–coupled receptors (GPCRs). A wide array of GPCRs has been shown to inhibit the activity of N-type calcium channels (Bean, 1989; Dunlap & Fischbach, 1978, 1981; for review, see Tedford & Zamponi, 2006). GPCR activation results in the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) in the G protein α subunit, leading to its dissociation or reorientation from the attached Gβγ dimer. Both Gα and Gβγ then initiate intracellular signaling cascades (for review, see Tedford & Zamponi, 2006). In the case of Cav2 channels, the Gβγ subunit exerts strong voltage-dependent inhibition (Bean, 1989; Herlitze et al., 1996; Ikeda, 1996). This occurs by direct interactions of Gβγ with the domain I–II linker and N-terminal regions of the channel (Agler et al., 2005; de Waard et al., 1997; Zamponi, Bourinet, Nelson, Nargeot, & Snutch, 1997), leading to stabilization of the closed state of the channel and failure to open readily in response to membrane depolarization (Patil et al., 1996).

In the context of pain, the most pertinent example is the direct voltage-dependent inhibition mediated by the family of opioid receptors (Mizoguchi, Watanabe, Sakurada, & Sakurada, 2012). The extended opioid receptor family comprises four members: the μ-opioid receptor (MOR), the κ-opioid receptor (KOR), and the δ-opioid receptor (DOR), along with the more distant relative called the nociceptin (NOP) receptor (for review, see McDonald & Lambert, 2005). Based on the distinct expression of these subtypes in different types of afferent fibers, MORs appear to preferentially regulate heat pain, whereas DORs preferentially regulate mechanical hypersensitivity (Scherrer et al., 2009). Each of the opioid receptor subtypes is capable of inhibiting N-type calcium channel activity via Gβγ (Gross & Macdonald., 1987; Heinke, Gingl, & Sandkühler, 2011; Moises, Rusin, & Macdonald, 1994; Morikawa et al., 1998; L. G. Motin, Bennett, & Christie., 1995; Toselli, Tosetti, & Taglietti, 1999; Yeon et al., 2004) and, moreover, appears to form physical signaling complexes with Cav2.2 channels and contributes to regulating channel trafficking to and from the plasma membrane (Altier et al., 2006; R. M. Evans et al., 2010). The efficacy of Gβγ inhibition is modulated by the formation of receptor heteromers (Costantino, Gomes, Stockton, Lim, & Devi, 2012; R. M. Evans et al., 2010; George et al., 2000; Gomes et al., 2000), with chronic morphine exposure promoting the formation of such complexes (Gupta et al., 2010). Constitutive activity of some of the receptor isoforms can lead to agonist-independent modulation of channel activity (Beedle et al., 2004; R. M. Evans et al., 2010). MORs may also regulate N-type channel activity via a parallel, voltage-independent pathway that involves tyrosine kinase phosphorylation (Andrade et al., 2010). The effects of receptor modulation vary with alternative splicing of exon 37 of Cav2.2 (Andrade et al., 2010). It is also worth noting that opioid receptors have multiple splice isoforms that may differentially contribute to analgesia (X. Y. Liu et al., 2011; Lu et al., 2018; Marrone et al., 2016; Piltonen et al., 2018).

Systemic or intrathecal delivery of agonists of either opioid receptor family member mediates analgesia (Courteix et al., 2004; Darland, Heinricher, & Grandy, 1998; Field et al., 1999; King, Rossi, Chang, Williams, & Pasternak, 1997; Mika, Przewłocki, & Przewłocka, 2001; Nozaki et al., 2012), and that may involve inhibition of N-type channel activity at dorsal horn synapses as well as supraspinal actions (Beaudry, Dubois, & Gendron, 2011; Diaz, Ruiz, Flórez, Hurlé, & Pazos, 1995; Goodchild, Nadeson, & Cohen, 2004; Kondo et al., 2005; Satoh et al., 1983). On the flip side, mice lacking the DOR exhibit mechanical allodynia, whereas the activation of these receptors with agonists such as SNC80, ADL5859, and ADL5747 protects from thermal and mechanical hypersensitivity (Nozaki et al., 2012). KOR agonists appear to have the advantage of not causing respiratory depression like that seen in response to MOR or DOR activation (Field et al., 1999; Freye, Hartung, & Schenk,1983).

The primary opioid receptor targeted in humans is the MOR—the pharmacological target of morphine (for review, see Mizoguchi et al., 2012). Morphine can be highly effective in suppressing pain; however, it has numerous issues, including adverse effects such as constipation and respiratory depression, along with the development of tolerance, dependence, and abuse (Frater et al., 1989)—a major problem, as evident from the growing opioid crisis around the globe. Opioids can also produce proalgesic effects, such as opioid-induced hyperalgesia, which may involve microglial signaling in the spinal dorsal horn (Burma et al., 2017; Ferrini et al., 2013; Varrassi et al., 2018). Adverse effects also include morphine-induced itch, which may involve interactions with the MOR1 splice isoform (Kuraishi, Yamaguchi, & Miyamoto, 2000; X. Y. Liu et al., 2011). Itch can be severe for some patients, thus further limiting the use of morphine.

Altogether, these data underscore the need to develop orally available, direct, N-type channel blockers, as noted previously in this chapter. Besides morphine, the KOR agonist pentazocine is approved for clinical use to treat pain (Goldstein, 1985). Several DOR agonists have been entered into clinical trials for pain. Of these, ADL5859, ADL5747, and NP2 passed phase I but were discontinued at phase II (Spahn & Stein, 2017).

Another GPCR with relevance to pain is the gamma-aminobutyric acid B (GABAB) receptor. Intrathecal delivery of the GABAB receptor agonist baclofen triggered analgesia in rodents (Terrence, Fromm, & Tenicela, 1985); however, the use of GABAB agonists in humans is limited by adverse central nervous system effects, such as increased food intake and seizures (Bortolato et al., 2010; Schuele et al., 2005). Nonetheless, here marine mollusks rear their heads again: The peptide Vc1.1, an α conotoxin from Conus victoriae, exhibits agonist activity at GABAB receptors (Berecki, McArthur, Cuny, Clark, & Adams, 2014; Callaghan et al., 2008; Callaghan & Adams, 2010; Cuny et al., 2012; Klimis et al., 2011), leading to inhibition of N-type calcium channels and analgesia in various rodent models of pain, including visceral pain (A. Castro et al., 2017; J. Castro et al., 2018; Klimis et al., 2011). Unfortunately, Vc1.1 failed a phase II clinical trial for neuropathic pain due to lack of efficacy. A cyclized version of this peptide has been generated for increased stability and showed oral efficacy in a rodent model of neuropathic pain (Carstens et al., 2011).

In summary, there are multiple approaches for targeting N-type calcium channel activity within the pain matrix, ranging from direct inhibitors of channel activity to channel modulators to regulators of channel trafficking and stability.

Cavα2δ Subunits as Targets for Treating Pain

Cavα2δ subunits are an important part of the HVA calcium channel complex and are involved in trafficking to the cell surface. The Cavα2δ-1 and Cavα2δ-2 subtypes are also pharmacological targets of the gabapentinoids gabapentin (Neurontin) and pregabalin (Lyrica), two blockbuster neuropathic pain drugs (Field, Li, & Schwarz, 2007; Rosenberg, Harrell, Ristic, Werner, & de Rosayro, 1997). Gabapentin binding to Cavα2δ-1 occurs at a specific site (Arg-217) (Gee et al., 1996), and mutant mice lacking this interaction site are resistant to the analgesic actions of gabapentin (Field et al., 2006; Lotarski et al., 2014). The analogous mutation in Cavα2δ-2 is ineffective, indicating that the former is the predominant clinical target for gabapentinoids. Moreover, note that gabapentin affinity for Cavα2δ-1 varies with splice isoform (Lana et al., 2014).

There appears to be little, if any, effect of acute application of gabapentinoids on N-type channel activity or synaptic transmission (Brown & Randall, 2005; Fehrenbacher, Taylor, & Vasko, 2003; Fink, Meder, Dooley, & Göthert, 2000; Hendrich et al., 2008; Quintero, Dooley, Pomerleau, Huettl, & Gerhardt, 2011; Rock, Kelly, & Macdonald, 1993). In contrast, chronic treatment with gabapentinoids may inhibit trafficking or recycling of N-type (and perhaps P/Q-type; Bayer, Ahmadi, & Zeilhofer, 2004) channels at synaptic sites in the dorsal horn, thus decreasing neurotransmitter release (Bauer et al., 2009, 2010; Tran‐Van‐Minh & Dolphin, 2010).

Recently, Cavα2δ-1 has also been shown to regulate N-methyl-d-aspartate (NMDA) receptor function at dorsal horn synapses, suggesting another possible mode of action of gabapentinoids on synaptic transmission in the primary afferent pain pathway (J. Chen et al., 2018). Cavα2δ subunits also appear to be involved in synapotogenesis (Eroglu et al., 2009; Yu, Gong, Kweon, Vo, & Luo, 2018), and it is therefore possible that gabapentinoids may act in part by modifying synaptic architecture in the spinal cord (K. W. Li et al., 2014) and perhaps the brain. Central actions of gabapentinoids have been described, including the regulation of descending noradrenergic modulation of pain signals from the locus coeruleus, along with reductions of neuronal activity within the central amygdala and a downstream loss of descending facilitation (Bee & Dickenson, 2008; Gonçalves & Dickenson, 2012; Suzuki et al., 2005; M. Tanabe et al., 2005; Takasu, Ono, & Tanabe, 2008). Despite intense investigations, exactly how gabapentinoid interactions with Cavα2δ modify transmission and perception of pain remains incompletely understood (for review, see Patel & Dickenson, 2016). Nonetheless, efforts to develop new Cavα2δ ligands continue with companies such as Novassay (Switzerland) (see also Blakemore et al., 2010).

Besides Cavα2δ, there are other cellular mechanisms that regulate the trafficking of N-type calcium channels to synaptic sites. One such example is collapsin response mediator protein 2 (CRMP2), a protein involved in both cell growth and synaptic function (Chi et al., 2009). CRMP2 physically interacts with Cav2.2 calcium channels, and overexpression of CRMP2 results in augmented N-type calcium currents in sensory neurons (Chi et al., 2009). Importantly, a cell-permeant peptide designed to disrupt the interaction between Cav2.2 and CRMP2 mediated analgesia in models of inflammatory and neuropathic pain (Brittain et al., 2011; Ripsch et al., 2012; Wilson et al., 2012). Whether this mechanism can be exploited toward the identification of small organic molecules with oral availability in humans remains to be determined. It should be noted that CRMP2 also regulates voltage-gated sodium channels in a SUMO(small ubiquitin modifier)ylation-dependent manner (François-Moutal et al., 2018; Moutal et al., 2017). This mechanism is currently being targeted by Regulonix, a small US-based biotechnology company.

T-Type Calcium Channels as Targets for Analgesics

T-type calcium channels can be inhibited by certain toxins derived from venomous spiders and scorpions. Kurtoxin, a peptide isolated from the venom of the scorpion Parabuthus transvaalicus mediates high-affinity inhibition of Cav3 calcium channels (Chuang, Jaffe, Cribbs, Perez-Reyes, & Swartz, 1998). Its mode of action is reminiscent of that described for ω-agatoxin IVA, which arrests calcium channels in their closed state (Sidach & Mintz, 2002). Kurtoxin, however, is not specific for T-type calcium cannels as it has actions on some HVA calcium channels and even sodium channels (Zhu, Wassall, Cunnane, & Teramoto, 2009). This is also true for other peptide toxins isolated from Parabuthus transvaalicus: KLI and KLII (Olamendi-Portugal et al., 2002). Protoxins I and II have been isolated from the Thrixopelma pruriens tarantula and are known blockers of sodium channels (Schmalhofer et al., 2008), but they also have gating modifier actions on T-type channels (Bladen, Hamid, Souza, & Zamponi, 2014; Edgerton, Blumenthal, & Hanck, 2010; Ohkubo, Yamazaki, & Kitamura, 2010). Another spider toxin with apparent selectivity for T-type calcium channels (PsPTx3) has been isolated from the Theraphosidae tarantula and may have utility as a pain therapeutic (French patent application FR2940973). However, similar to that for N-type channel-blocking peptides, T-type channel-blocking toxins may be of limited utility due to their inability to cross the blood–brain barrier.

A number of small organic molecule inhibitors of T-type calcium channels have been identified. The diuretic amiloride has been reported to inhibit Cav3.2 channels with 10-fold higher affinity compared to Cav3.1 and Cav3.3 channels (Lopez-Charcas, Rivera, & Gomora, 2012); however, this compound blocks other targets, including sodium channels, and is by no means a selective T-type calcium channel inhibitor (Kleyman & Cragoe, 1988; Manev, Bertolino, & DeErausquin, 1990). The antiepileptic agent ethosuximide blocks all Cav3 channel subtypes with low affinity in a state-dependent manner (Gomora, Daud, Weiergräber, & Perez-Reyes, 2001; Huguenard, 2002), and intrathecal or intraperitoneal delivery of ethosuximide has been shown to mediate analgesia in rodent models of neuropathic pain (Y. L. Chen et al., 2015; Dogrul et al., 2003; Flatters and Bennett, 2004; Hamidi et al., 2012). Along these lines, mibefradil was initially purported as a selective inhibitor of T-type channels (Ertel & Clozel, 1997; Mishra & Hermsmeyer, 1994) and was FDA approved as an antihypertensive, but was later withdrawn due to drug–drug interactions (Mullins et al., 1998). It inhibits neuropathic pain when delivered intrathecally (Dogrul et al., 2003).

Several more recent derivatives of mibefradil have been explored as possible analgesics. These include NNC55-0396 (Bui, Quesada, Handforth, & Hankinson, 2008), as well as TTA-A2 and TTA-P2 (Choe et al., 2011; François et al., 2013). These compounds mediate state-dependent blocking of Cav3 channels and were efficacious in rodent models of pain. Several diphenyl-butyl piperidines agonists of dopamine receptors have been shown to mediate use-dependent blocking of Cav3 channels (Enyeart, Biagi, Day, Sheu, & Maurer, 1990; Santi et al., 2002). Derivatives of these compounds based on rational drug design led to the development of several high-affinity, T-type calcium channel blockers, including Z944 (Tringham et al., 2012), which successfully exhibited efficacy in a phase Ib clinical trial for induced inflammatory pain (M. Lee, 2014).

Another blocker of T-type calcium channels, ABT-639, has shown efficacy in rodent models of neuropathic pain (Jarvis et al., 2014). This compound subsequently entered into three randomized clinical trials, but showed no efficacy in either diabetic neuropathy pain (Serra et al., 2015; Ziegler, Duan, An, Thomas, & Nothaft, 2015) or an intradermal capsaicin model (M. Wallace, Duan, Liu, Locke, & Nothaft, 2016). These failures, in our view, do not constitute an invalidation of Cav3 channels as potential targets for analgesics but are more likely related to these specific compounds.

There are continuing efforts to develop small organic molecular inhibitors of T-type calcium channels. Some of these are based on the observation that certain endocannabinoids are potent T-type channel inhibitors (Barbara et al., 2009; Chemin, Monteil, Perez-Reyes, Nargeot, & Lory, 2001), and that modification of the chemical structures of cannabinoid-like compounds has been shown to increase selectivity of these compounds for T-type channels over cannabinoid receptors and to exhibit efficacy in rodent models of neuropathic and inflammatory (Bladen et al., 2015; Gadotti et al., 2013; You, Gadotti, Petrov, Zamponi, & Diaz, 2011). We have recently reviewed in depth the additional compounds that target T-type calcium channels for the purpose of developing pain therapeutics (Snutch & Zamponi, 2018). These include the 3,4-dihydroquinazoline KYS-05090S (H. B. Kang et al., 2012; M’Dahoma et al., 2016), as well as disubstituted piperazine derivatives and 6-aryl-connected-3-N-substituted azabicyclo[3.1.0]hexane derivatives and aryl(1,5-disubstituted-pyrazol-3-yl)methyl sulfonamides with T-type calcium channel-blocking properties and efficacy in rodent models of neuropathic pain (J.H. Kim & Nam, 2016; J. H. Kim, Keum, Chung, & Nam, 2016). Finally, RQ-00311651 appears to be effective as an oral analgesic in models of neuropathic pain (Sekiguchi et al., 2016). Whether any of these compounds will advance to clinical studies remains to be seen.

As noted, T-type calcium channels are regulated by the deubiquitinase USP5. Akin to that described for CRMP2 modulation of N-type channels, disrupting Cav3.2 interactions with USP5 may be a viable strategy toward developing analgesics that do not themselves block Cav3.2 channels, but instead interfere with their aberrant regulation. Gadotti and colleagues (2015) devised a screen based on an enzyme-linked immunosorbent assay (ELISA) for small organic molecule disruptors of the Cav3.2–USP5 interaction. A partnership with the Center for Drug Research and Development (CDRD, Vancouver, Canada) identified several hits, which were then successfully tested in mouse models of inflammatory and neuropathic pain. Further efforts at CDRD are under way to develop new analgesics based on targeting USP5.

Altogether, T-type calcium channels are likely suitable pharmacological targets for the development of new pain therapeutics. Although there have been setbacks with compounds such as ABT-639, considerable medicinal chemistry efforts continue toward identifying Cav3.2 state-dependent blockers.

R Type as Possible Targets for Treating Pain

Like T-type calcium channels, Cav2.3 R-type calcium channels contribute to regulation of neuronal excitability and partake in synaptic transmission (Castro et al., 2009; Gasparini, Kasyanov, Pietrobon, Voronin, & Cherubini, 2001; Kamp et al., 2005; Lirk et al., 2008; Myoga & Regehr, 2011; Park et al., 2010; L. G. Wu, Borst, & Sakmann, 1998; Zaman et al., 2011). Cav2.3 gene null mice exhibit hyposensitivity in inflammatory pain models (Saegusa et al., 2000, 2002), and Cav2.3 channels are expressed in DRG neurons (Fang, Hwang, Kim, Jung, & Oh, 2010; Fang et al., 2007). Collectively, this suggests that Cav2.3 channels may contribute to afferent pain signaling and thus may be potential targets for the development of analgesics. This is further underscored by observations that intrathecal delivery of the Cav2.3 antagonist SNX-482, a gating modifier peptide isolated from the tarantula Hysterocrates gigas, resulted in analgesia in neuropathic pain models (Matthews et al., 2007). It is important to note that SNX-482 has actions on other targets, such as L-type calcium channels (Bourinet et al., 2001). Similar considerations apply to the spider toxin TX3.3, which blocks both R-type and P/Q-type channel peptide and is efficacious in models of neuropathic pain (Dalmolin et al., 2011, 2017; Silva et al., 2015). Regardless, these considerations suggest Cav2.3 channels as a possible target for the development of analgesics; however, to date there appears to be no available small organic inhibitor entirely selective for these channels.


Voltage-gated calcium channels are important mediators of transmission, transduction, and processing of pain signals. Several calcium channel subtypes are dysregulated during chronic pain conditions, giving rise to increased neuronal excitability and synaptic transmission. N-type calcium channels, Cav3.2 T-type calcium channels, and the Cavα2δ subunit are validated targets for the development and clinical use of small organic analgesics, with R-type channels showing potential as possible targets based on preclinical studies.


Abbadie, C., McManus, O. B., Sun, S. Y., Bugianesi, R. M., Dai, G., Haedo, R. J., … Duffy JL (2010). Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker. The Journal of Pharmacology and Experimental Therapeutics, 334(2), 545–555.Find this resource:

Adams, D. J., Smith, A. B., Schroeder, C. I., Yasuda, T., & Lewis, R. J. (2003). Omega-conotoxin CVID inhibits a pharmacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals. The Journal of Biological Chemistry, 278(6), 4057–4062.Find this resource:

Agler, H. L., Evans, J., Tay, L. H., Anderson, M. J., Colecraft, H. M., & Yue, D. T. (2005). G protein-gated inhibitory module of N-type (ca(v)2.2) Ca2+ channels. Neuron. 46(6), 891–904.Find this resource:

Altier, C., Garcia-Caballero, A., Simms, B., You, H., Chen, L., Walcher, J., … Zamponi, G. W. (2011). The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels. Nature Neuroscience, 14(2), 173–180.Find this resource:

Altier, C., Khosravani, H., Evans, R. M., Hameed, S., Peloquin, J. B., Vartian, B. A., … Zamponi GW (2006). ORL1 receptor-mediated internalization of N-type calcium channels. Nature Neuroscience, 9(1), 31–40.Find this resource:

Andrade, A., Denome, S., Jiang, Y. Q., Marangoudakis, S., & Lipscombe, D. (2010). Opioid inhibition of N-type Ca2+ channels and spinal analgesia couple to alternative splicing. Nature Neuroscience, 13(10), 1249–1256.Find this resource:

Angelotti, T., & Hofmann, F. (1996). Tissue-specific expression of splice variants of the mouse voltage-gated calcium channel alpha2/delta subunit. FEBS Letters, 397(2–3), 331–337.Find this resource:

Atanassoff, P. G., Hartmannsgruber, M. W., Thrasher, J., Wermeling, D., Longton, W., Gaeta, R., … Luther, R. R. (2000). Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. Regional Anesthesia and Pain Medicine, 25(3), 274–278.Find this resource:

Bannister, R. A., & Beam, K. G. (2013). CaV1.1: The atypical prototypical voltage-gated Ca2+ channel. Biochimica et Biophysica Acta, 1828(7), 1587–1597.Find this resource:

Barbara, G., Alloui, A., Nargeot, J., Lory, P., Eschalier, A., Bourinet, E., & Chemin, J. (2009). T-type calcium channel inhibition underlies the analgesic effects of the endogenous lipoamino acids. Neuroscience, 29(42), 13106–13114.Find this resource:

Barclay, J., Balaguero, N., Mione, M., Ackerman, S. L., Letts, V. A., Brodbeck, J., … Rees, M. (2001). Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 21(16), 6095–6104.Find this resource:

Bauer, C. S., Nieto-Rostro, M., Rahman, W., Tran-Van-Minh, A., Ferron, L., Douglas, L., … Dolphin, A. C. (2009). The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 29(13), 4076–4088.Find this resource:

Bauer, C. S., Rahman, W., Tran-van-Minh, A., Lujan, R., Dickenson, A. H., & Dolphin, A. C. (2010). The anti-allodynic alpha(2)delta ligand pregabalin inhibits the trafficking of the calcium channel alpha(2)delta-1 subunit to presynaptic terminals in vivo. Biochemical Society Transactions, 38(2), 525–528.Find this resource:

Bayer, K., Ahmadi, S., & Zeilhofer, H. U. (2004). Gabapentin may inhibit synaptic transmission in the mouse spinal cord dorsal horn through a preferential block of P/Q-type Ca2+ channels. Neuropharmacology, 46(5), 743–749.Find this resource:

Bean, B. P. (1989). Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence. Nature, 340(6229), 153–156.Find this resource:

Beaudry, H., Dubois, D., & Gendron, L. (2011). Activation of spinal mu- and delta-opioid receptors potently inhibits substance P release induced by peripheral noxious stimuli. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31(37), 13068–13077.Find this resource:

Bee, L. A., & Dickenson, A. H. (2008). Descending facilitation from the brainstem determines behavioural and neuronal hypersensitivity following nerve injury and efficacy of pregabalin. Pain, 140(1), 209–223.Find this resource:

Beedle, A. M., McRory, J. E., Poirot, O., Doering, C. J., Altier, C., Barrere, C., … Zamponi, G. W. (2004). Agonist-independent modulation of N-type calcium channels by ORL1 receptors. Nature Neuroscience, 7(2), 118–125.Find this resource:

Bell, T. J., Thaler, C., Castiglioni, A. J., Helton, T. D., & Lipscombe, D. (2004). Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron, 41(1), 127–138.Find this resource:

Berecki, G., McArthur, J. R., Cuny, H., Clark, R. J., & Adams, D. J. (2014). Differential Cav2.1 and Cav2.3 channel inhibition by baclofen and α-conotoxin Vc1.1 via GABAB receptor activation. The Journal of General Physiology, 143(4), 465–479.Find this resource:

Berecki, G., Motin, L., Haythornthwaite, A., Vink, S., Bansal, P., Drinkwater, R., … Adams, D. J. (2010). Analgesic (omega)-conotoxins CVIE and CVIF selectively and voltage-dependently block recombinant and native N-type calcium channels. Molecular Pharmacology, 77(2), 139–148.Find this resource:

Bladen, C., Gadotti, V. M., Gündüz, M. G., Berger, N. D., Şimşek, R., Şafak, C., & Zamponi, G. W. (2015). 1,4-Dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain. Pflugers Archiv: European Journal of Physiology, 467(6), 1237–1247.Find this resource:

Bladen, C., Hamid, J., Souza, I. A., & Zamponi, G. W. (2014). Block of T-type calcium channels by protoxins I and II. Molecular Brain, 9(7), 36.Find this resource:

Blakemore, D. C., Bryans, J. S., Carnell, P., Field, M. J., Kinsella, N., Kinsora, J. K., … Williams, S. C. (2010). Synthesis and in vivo evaluation of 3,4-disubstituted gababutins. Bioorganic & Medicinal Chemistry Letters, 20(1), 248–251.Find this resource:

Boroujerdi, A., Kim, H. K., Lyu, Y. S., Kim, D. S., Figueroa, K. W., Chung, J. M., & Luo, Z. D. (2008). Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain. Pain, 139(2), 358–366.Find this resource:

Boroujerdi, A., Zeng, J., Sharp, K., Kim, D., Steward, O., & Luo, Z. D. (2011). Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states. Pain 152(3), 649–655.Find this resource:

Bortolato, M., Barberini, L., Puligheddu, M., Muroni, A., Maleci, A., Ennas, F., … Marrosu, F. (2010). Involvement of GABA in mirror focus: A case report. Epilepsy Research, 90(3), 300–303.Find this resource:

Bourinet, E., Alloui, A., Monteil, A., Barrère, C., Couette, B., Poirot, O., … Nargeot, J. (2005). Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. The EMBO Journal, 24(2), 315–324.Find this resource:

Bourinet, E., Altier, C., Hildebrand, M. E., Trang, T., Salter, M. W., & Zamponi, G. W. (2014). Calcium-permeable ion channels in pain signaling. Physiological Reviews, 94(1), 81–140.Find this resource:

Bourinet, E., Stotz, S. C., Spaetgens, R. L., Dayanithi, G., Lemos, J., Nargeot, J., & Zamponi, G. W. (2001). Interaction of SNX482 with domains III and IV inhibits activation gating of alpha(1E) (Ca(V)2.3) calcium channels. Biophysical Journal, 81(1), 79–88.Find this resource:

Bowersox, S. S., & Luther, R. (1998). Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus. Toxicon: Official Journal of the International Society on Toxinology, 36(11), 1651–1658.Find this resource:

Brennan, K. C., & Pietrobon, D. (2018). A systems neuroscience approach to migraine. Neuron, 97(5), 1004–1021.Find this resource:

Brittain, J. M., Duarte, D. B., Wilson, S. M., Zhu, W., Ballard, C., Johnson, P. L., … Khanna, R. (2011). Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex. Nature Medicine, 17(7), 822–829.Find this resource:

Brodbeck, J., Davies, A., Courtney, J. M., Meir, A., Balaguero, N., Canti, C., … Dolphin, A. C. (2002). The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated alpha 2 delta-2 protein with abnormal function. The Journal of Biological Chemistry, 277(10), 7684–7693.Find this resource:

Brown, J. T., & Randall, A. (2005). Gabapentin fails to alter P/Q-type Ca2+ channel-mediated synaptic transmission in the hippocampus in vitro. Synapse, 55(4), 262–269.Find this resource:

Bui, P. H., Quesada, A., Handforth, A., & Hankinson, O. (2008). The mibefradil derivative NNC55-0396, a specific T-type calcium channel antagonist, exhibits less CYP3A4 inhibition than mibefradil. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 36(7), 1291–1299.Find this resource:

Buraei, Z., &Yang, J. (2010). The ß subunit of voltage-gated Ca2+ channels. Physiological Reviews, 90(4), 1461–1506.Find this resource:

Burma, N. E., Bonin, R. P., Leduc-Pessah, H., Baimel, C., Cairncross, Z. F., Mousseau, M., … Trang, T. (2017). Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. Nature Medicine, 23(3), 355–360.Find this resource:

Callaghan, B., & Adams, D. J. (2010). Analgesic alpha-conotoxins Vc1.1 and RgIA inhibit N-type calcium channels in sensory neurons of alpha9 nicotinic receptor knockout mice. Channels, 4(1), 51–54.Find this resource:

Callaghan, B., Haythornthwaite, A., Berecki, G., Clark, R. J., Craik, D. J., & Adams, D. J. (2008). Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(43), 10943–10951.Find this resource:

Cantí, C., Nieto-Rostro, M., Foucault, I., Heblich, F., Wratten, J., Richards, M. W., … Dolphin, A. (2005). The metal-ion-dependent adhesion site in the Von Willebrand factor-A domain of alpha2delta subunits is key to trafficking voltage-gated Ca2+ channels. Proceedings of the National Academy of Sciences of the United States of America, 102(32), 11230–11235.Find this resource:

Carstens, B. B., Clark, R. J., Daly, N. L., Harvey, P. J., Kaas, Q., & Craik, D. J. (2011). Engineering of conotoxins for the treatment of pain. Current Pharmaceutical Design, 17(38), 4242–4253.Find this resource:

Castiglioni, A. J., Raingo, J., & Lipscombe, D. (2006). Alternative splicing in the C-terminus of CaV2.2 controls expression and gating of N-type calcium channels. The Journal of Physiology, 576(Pt. 1), 119–134.Find this resource:

Castro, A., Andrade, A., Vergara, P., Segovia, J., Aguilar, J., Felix, R., & Delgado-Lezama, R. (2009). Involvement of R-type Ca2+ channels in neurotransmitter release from spinal dorsolateral funiculus terminals synapsing motoneurons. The Journal of Compareative Neurology, 513(2), 188–196.Find this resource:

Castro, A., Raver, C., Li, Y., Uddin, O., Rubin, D., Ji, Y., … Keller, A. (2017). Cortical regulation of nociception of the trigeminal nucleus caudalis. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 37(47), 11431–11440.Find this resource:

Castro, J., Grundy, L., Deiteren, A., Harrington, A. M., O’Donnell, T., Maddern, J., … Brierley, S. M. (2018). Cyclic analogues of α-conotoxin Vc1.1 inhibit colonic nociceptors and provide analgesia in a mouse model of chronic abdominal pain. British Journal of Pharmacology, 175(12), 2384–2398.Find this resource:

Catterall, W. A., Leal, K., & Nanou, E. (2013). Calcium channels and short-term synaptic plasticity. The Journal of Biological Chemistry, 288(15), 10742–10749.Find this resource:

Catterall, W. A., Perez-Reyes, E., Snutch, T. P., & Striessnig, J. (2005). International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacological Reviews, 57(4), 411–425.Find this resource:

Chaplan, S. R., Pogrel, J. W., & Yaksh, T. L. (1994). Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia The Journal of Pharmacology and Experimental Therapeutics, 269(3), 1117–1123.Find this resource:

Chemin, J., Monteil, A., Bourinet, E., Nargeot, J., & Lory, P. (2001). Alternatively spliced alpha(1G) (Ca(V)3.1) intracellular loops promote specific T-type Ca(2+) channel gating properties. Biophysical Journal, 80(3), 1238–1250.Find this resource:

Chemin, J., Monteil, A., Perez-Reyes, E., Nargeot, J., & Lory, P. (2001). Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. The EMBO Journal, 20(24), 7033–7040.Find this resource:

Chen, J., Li, L., Chen, S. R., Chen, H., Xie, J. D., Sirrieh, R. E., … Pan, H. L. (2018). The α2δ-1-NMDA receptor complex is critically involved in neuropathic pain development and gabapentin therapeutic actions. Cell Reports, 22(9), 2307–2321.Find this resource:

Chen, Y. L., Tsaur, M. L., Wang, S. W., Wang, T. Y., Hung, Y. C., Lin, C., … Cheng, J. K. (2015). Chronic intrathecal infusion of mibefradil, ethosuximide and nickel attenuates nerve ligation-induced pain in rats. British Journal of Anaesthesia, 115(1), 105–111.Find this resource:

Chi, X. X., Schmutzler, B. S., Brittain, J. M., Wang, Y., Hingtgen, C. M., Nicol, G. D., & Khanna, R. (2009). Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons. Journal of Cell Science, 122, 4351–4362.Find this resource:

Choe, W., Messinger, R. B., Leach, E., Eckle, V. S., Obradovic, A., Salajegheh, R., … Todorovic, S. M. (2011). TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. Molecular Pharmacology, 80(5), 900–910.Find this resource:

Choi, S., Na, H. S., Kim, J., Lee, J., Lee, S., Kim, D., … Shin, H. S. (2007) Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels. Genes, Brain and Behavior, 6(5), 425–431.Find this resource:

Chuang, R. S., Jaffe, H., Cribbs, L., Perez-Reyes, E., & Swartz, K. J. (1998). Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin. Nature Neuroscience, 1(8), 668–674.Find this resource:

Cizkova, D., Marsala, J., Lukacova, N., Marsala, M., Jergova, S., Orendacova, J., & Yaksh, T. L. (2002). Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury. Experimental Brain Research, 147(4), 456–463.Find this resource:

Costantino, C. M., Gomes, I., Stockton, S. D., Lim, M. P., & Devi, L. A. (2012). Opioid receptor heteromers in analgesia. Expert Reviews in Molecular Medicine, 10(14), e9.Find this resource:

Costigan, M., Befort, K., Karchewski, L., Griffin, R. S., D’Urso, D., Allchorne, A., … Woolf, C. J. (2002). Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neuroscience, 3, 16.Find this resource:

Coulter, D. A., Huguenard, J. R., & Prince, D. A. (1989). Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Annals of Neurology, 25(6), 582–593.Find this resource:

Courteix, C., Coudoré-Civiale, M. A., Privat, A. M., Pélissier, T., Eschalier, A., & Fialip, J. (2004). Evidence for an exclusive antinociceptive effect of nociceptin/orphanin FQ, an endogenous ligand for the ORL1 receptor, in two animal models of neuropathic pain. Pain, 110(1–2), 236–245.Find this resource:

Cribbs, L. L., Lee, J. H., Yang, J., Satin, J., Zhang, Y., Daud, A., … Perez-Reyes, E. (1998). Cloning and characterization of alpha1H from human heart, a member of the T-type Ca2+ channel gene family. Circulation Research, 83(1), 103–109.Find this resource:

Cuny, H., de Faoite, A., Huynh, T. G., Yasuda, T., Berecki, G., & Adams, D. J. (2012). γ-Aminobutyric acid type B (GABAB) receptor expression is needed for inhibition of N-type (Cav2.2) calcium channels by analgesic alpha-conotoxins. The Journal of Biological Chemistry, 287(28), 23948–23957.Find this resource:

Dalmolin, G. D., Bannister, K., Gonçalves, L., Sikandar, S., Patel, R., Cordeiro, M. D. N., … Dickenson, A. H. (2017). Effect of the spider toxin Tx3-3 on spinal processing of sensory information in naive and neuropathic rats: An in vivo electrophysiological study. Pain Reports, 2(4), e610.Find this resource:

Dalmolin, G. D., Silva, C. R., Rigo, F. K., Gomes, G. M., Cordeiro Mdo, N., Richardson, M., … Ferreira, J. (2011). Antinociceptive effect of Brazilian armed spider venom toxin Tx3-3 in animal models of neuropathic pain. Pain, 152(10), 2224–2232.Find this resource:

Darland, T., Heinricher, M. M., & Grandy, D. K. (1998). Orphanin FQ/nociceptin: A role in pain and analgesia, but so much more. Trends in Neurosciences, 21(5), 215–221.Find this resource:

Davies, A., Kadurin, I., Alvarez-Laviada, A., Douglas, L., Nieto-Rostro, M., Bauer, C. S., … Dolphin, A. C. (2010). The alpha2delta subunits of voltage-gated calcium channels form GPI-anchored proteins, a posttranslational modification essential for function. Proceedings of the National Academy of Sciences of the United States of America, 107(4), 1654–1659.Find this resource:

De Waard, M., Liu, H., Walker, D., Scott, V. E., Gurnett, C. A., & Campbell, K. P. (1997). Direct binding of G-protein betagamma complex to voltage-dependent calcium channels. Nature, 385(6615), 446–450.Find this resource:

Diaz, A., & Dickenson, A. H. (1997). Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal horn neurones produced by subcutaneous formalin inflammation. Pain, 69(1–2), 93–100.Find this resource:

Diaz, A., Ruiz, F., Flórez, J., Hurlé, M. A., & Pazos, A. (1995). Mu-opioid receptor regulation during opioid tolerance and supersensitivity in rat central nervous system. The Journal of Pharmacology and Experimental Therapeutics, 274(3), 1545–1551.Find this resource:

Dogrul, A., Gardell, L. R., Ossipov, M. H., Tulunay, F. C., Lai, J., & Porreca, F. (2003). Reversal of experimental neuropathic pain by T-type calcium channel blockers. Pain, 105(1–2), 159–168.Find this resource:

Dubel, S. J., Starr, T. V., Hell, J., Ahlijanian, M. K., Enyeart, J. J., Catterall, W. A., & Snutch, T. P. (1992). Molecular cloning of the alpha-1 subunit of an omega-conotoxin-sensitive calcium channel. Proceedings of the National Academy of Sciences of the United States of America, 89(11), 5058–5062.Find this resource:

Dunlap, K., & Fischbach, G. D. (1978). Neurotransmitters decrease the calcium component of sensory neuron action potentials. Nature, 276(5690), 837–839.Find this resource:

Dunlap, K., & Fischbach, G. D. (1981). Neurotransmitters decrease the calcium conductance activated by depolarization of embryonic chick sensory neurons. The Journal of Physiology, 317, 519–535.Find this resource:

Edgerton, G. B., Blumenthal, K. M., & Hanck, D. A. (2010). Inhibition of the activation pathway of the T-type calcium channel Ca(V)3.1 by ProTxII Toxicon: Official JOurnal of the International Society on Toxinology, 56(4), 624–636.Find this resource:

Enyeart, J. J., Biagi, B. A., Day, R. N., Sheu, S. S., & Maurer, R. A. (1990). Blockade of low and high threshold Ca2+ channels by diphenylbutylpiperidine antipsychotics linked to inhibition of prolactin gene expression. The Journal of Biological Chemistry, 265(27), 16373–16379.Find this resource:

Eroglu, C., Allen, N. J., Susman, M. W., O’Rourke, N. A., Park, C. Y., Ozkan, E., … Barres, B. A. (2009). Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell, 139(2), 380–392.Find this resource:

Ertel, S. I., & Clozel, J. P. (1997). Mibefradil (Ro 40-5967), the first selective T-type Ca2+ channel blocker. Expert Opinion on Investigational Drugs, 6(5), 569–582.Find this resource:

Evans, J. G., & Todorovic, S. M. (2015). Redox and trace metal regulation of ion channels in the pain pathway. The Biochemical Journal, 470(3), 275–280.Find this resource:

Evans, R. M., You, H., Hameed, S., Altier, C., Mezghrani, A., Bourinet, E., & Zamponi, G. W. (2010). Heterodimerization of ORL1 and opioid receptors and its consequences for N-type calcium channel regulation. The Journal of Biological Chemistry, 285(2), 1032–1040.Find this resource:

Fang, Z., Hwang, J. H., Kim, J. S., Jung, S. J., & Oh, S. B. (2010). R-type calcium channel isoform in rat dorsal root ganglion neurons. Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 14(1), 45–49.Find this resource:

Fang, Z., Park, C. K., Li, H. Y., Kim, H. Y., Park, S. H., Jung, S. J., … Miller, R. J. (2007). Molecular basis of Ca(v)2.3 calcium channels in rat nociceptive neurons. The Journal of Biological Chemistry, 282(7), 4757–4764.Find this resource:

Favereaux, A., Thoumine, O., Bouali-Benazzouz, R., Roques, V., Papon, M. A., Salam, S. A., … Landry, M. (2011). Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: Role in pain. The EMBO Journal, 30(18), 3830–3841.Find this resource:

Fehrenbacher, J. C., Taylor, C. P., & Vasko, M. R. (2003). Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain, 105(1–2), 133–141.Find this resource:

Ferrini, F., Trang, T., Mattioli, T. A., Laffray, S., Del’Guidice, T., Lorenzo, L. E., … De Koninck, Y. (2013). Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl- homeostasis. Nature Neuroscience, 16(2), 183–192.Find this resource:

Field, M. J., Carnell, A. J., Gonzalez, M. I., McCleary, S., Oles, R. J., Smith, R., … Singh, L. (1999). Enadoline, a selective kappa-opioid receptor agonist shows potent antihyperalgesic and antiallodynic actions in a rat model of surgical pain. Pain, 80(1–2), 383–389.Find this resource:

Field, M. J., Cox, P. J., Stott, E., Melrose, H., Offord, J., Su, T. Z., … Williams, D. (2006). Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proceedings of the National Academy of Sciences of the United States of America, 103(46), 17537–17542.Find this resource:

Field, M. J., Li, Z., & Schwarz, J. B. (2007). Ca2+ channel alpha2-delta ligands for the treatment of neuropathic pain. Journal of Medicinal Chemistry, 50(11), 2569–2575.Find this resource:

Fink, K., Meder, W., Dooley, D. J., & Göthert, M. (2000). Inhibition of neuronal Ca(2+) influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices. British Journal of Pharmacology, 130(4), 900–906.Find this resource:

Flatters, S. J., & Bennett, G. J. (2004). Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain, 109(1–2), 150–161.Find this resource:

Fossat, P., Dobremez, E., Bouali-Benazzouz, R., Favereaux, A., Bertrand, S. S., Kilk, K., … Nagy, F. (2010). Knockdown of L calcium channel subtypes: Differential effects in neuropathic pain. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30(3), 1073–1085.Find this resource:

François, A., Kerckhove, N., Meleine, M., Alloui, A., Barrere, C., Gelot, A., … Bourinet, E. (2013). State-dependent properties of a new T-type calcium channelblocker enhance Ca(V)3.2 selectivity and support analgesic effects. Pain, 154(2), 283–293.Find this resource:

François, A., Schüetter, N., Laffray, S., Sanguesa, J., Pizzoccaro, A., Dubel, S., … Bourinet, E. (2015). The low-threshold calcium channel Cav3.2 determines low-threshold mechanoreceptor function. Cell Reports, pii, S2211-1247(14)01095-X.Find this resource:

François-Moutal, L., Dustrude, E. T., Wang, Y., Brustovetsky, T., Dorame, A., Ju, W., … Khanna, R. (2018). Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases NaV1.7 currents and reverses experimental neuropathic pain. Pain, 159(10), E8443–E8452.Find this resource:

Frater, R. A., Moores, M. A., Parry, P., & Hanning, C. D. (1987) Analgesia-induced respiratory depression: Comparison of meptazinol and morphine in the postoperative period. British Journal of Anaesthesia, 63(3), 260–265.Find this resource:

Freye, E., Hartung, E., & Schenk, G. K. (1983). Bremazocine: An opiate that induces sedation and analgesia without respiratory depression. Anesthesia and Analgesia, 62(5), 483–488.Find this resource:

Gadotti, V. M., Caballero, A. G., Berger, N. D., Gladding, C. M., Chen, L., Pfeifer, T. A., & Zamponi, G. W. (2015). Small organic molecule disruptors of Cav3.2—USP5 interactions reverse inflammatory and neuropathic pain. Molecular Pain, 11, 12.Find this resource:

Gadotti, V. M., You, H., Petrov, R. R., Berger, N. D., Diaz, P., & Zamponi, G. W. (2013). Analgesic effect of a mixed T-type channel inhibitor/CB2 receptor agonist. Molecular Pain, 9, 32.Find this resource:

Garcia-Caballero, A., Gadotti, V. M., Chen, L., & Zamponi, G. W. (2016). A cell-permeant peptide corresponding to the cUBP domain of USP5 reverses inflammatory and neuropathic pain. Molecular Pain, 12, pii: 1744806916642444.Find this resource:

García-Caballero, A., Gadotti, V. M., Stemkowski, P., Weiss, N., Souza, I. A., Hodgkinson, V., … Zamponi, G. W. (2014). The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3.2 channel activity. Neuron, 83(5), 1144–1158.Find this resource:

Gasparini, S., Kasyanov, A. M., Pietrobon, D., Voronin, L. L., & Cherubini, E. (2001). Presynaptic Rtype calcium channels contribute to fast excitatory synaptic transmission in the rat hippocampus. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 21(22), 8715–8721.Find this resource:

Gee, N. S., Brown, J. P., Dissanayake, V. U., Offord, J., Thurlow, R., & Woodruff, G. N. (1996). The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. The Journal of Biological Chemistry, 271(10), 5768–5776.Find this resource:

George, S. R., Fan, T., Xie, Z., Tse, R., Tam, V., Varghese, G., & O’Dowd, B. F. (2000). Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. The Journal of Biological Chemistry, 275(34), 26128–26135.Find this resource:

Goldstein, G. (1985). Pentazocine. Drug and Alcohol Dependence, 14, 313–323.Find this resource:

Gomes, I., Jordan, B. A., Gupta, A., Trapaidze, N., Nagy, V., & Devi, L. A. (2000). Heterodimerization of mu and delta opioid receptors: A role in opiate synergy. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 20(22), RC110.Find this resource:

Gomora, J. C., Daud, A. N., Weiergräber, M., & Perez-Reyes, E. (2001). Block of cloned human T-type calcium channels by succinimide antiepileptic drugs. Molecular Pharmacology, 60(5), 1121–1132.Find this resource:

Gonçalves, L., & Dickenson, A. H. (2012). Asymmetric time-dependent activation of right central amygdala neurones in rats with peripheral neuropathy and pregabalin modulation. The European Journal of Neuroscience, 36(9), 3204–3213.Find this resource:

Goodchild, C. S., Nadeson, R., & Cohen, E. (2004). Supraspinal and spinal cord opioid receptors are responsible for antinociception following intrathecal morphine injections. European Journal of Anaesthesiology, 21(3), 179–185.Find this resource:

Gross, R. A., & Macdonald, R. L. (1987). Dynorphin A selectively reduces a large transient (N-type) calcium current of mouse dorsal root ganglion neurons in cell culture. Proceedings of the National Academy of Sciences of the United States of America, 84(15), 5469–5473.Find this resource:

Gupta, A., Mulder, J., Gomes, I., Rozenfeld, R., Bushlin, I., Ong, E., … Devi, L. A. (2010). Increased abundance of opioid receptor heteromers after chronic morphine administration. Science Signaling, 3(131), ra54.Find this resource:

Gurnett, C. A., De Waard, M., & Campbell, K. P. (1996). Dual function of the voltage-dependent Ca2+ channel alpha 2 delta subunit in current stimulation and subunit interaction. Neuron, 16(2), 431–440.Find this resource:

Gurnett, C. A., Felix, R., & Campbell, K. P. (1997). Extracellular interaction of the voltage-dependent Ca2+ channel alpha2delta and alpha1 subunits. The Journal of Biological Chemistry, 272(29), 18508–18512.Find this resource:

Hamidi, G. A., Ramezani, M. H., Arani, M. N., Talaei, S. A., Mesdaghinia, A., & Banafshe, H. R. (2012). Ethosuximide reduces allodynia and hyperalgesia and potentiates morphine effects in the chronic constriction injury model of neuropathic pain. European Journal of Pharmacology, 674(2–3), 260–264.Find this resource:

Hatakeyama, S., Wakamori, M., Ino, M., Miyamoto, N., Takahashi, E., Yoshinaga, T., … Shoji, S. (2001). Differential nociceptive responses in mice lacking the alpha(1B) subunit of N-type Ca(2+) channels. Neuroreport, 12(11), 2423–2427.Find this resource:

Heinke, B., Gingl, E., & Sandkühler, J. (2011). Multiple targets of μ-opioid receptor-mediated presynaptic inhibition at primary afferent Aδ- and C-fibers. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31(4), 1313–1322.Find this resource:

Hendrich, J., Van Minh, A. T., Heblich, F., Nieto-Rostro, M., Watschinger, K., Striessnig, J., … Dolphin, A. C. (2008). Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin. Proceedings of the National Academy of Sciences of the United States of America, 105(9), 3628–3633.Find this resource:

Herlitze, S., Garcia, D. E., Mackie, K., Hille, B., Scheuer, T., & Catterall, W. A. (1996). Modulation of Ca2+ channels by G-protein beta gamma subunits. Nature, 380(6571), 258–262.Find this resource:

Hille, B. (1977). Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction. The Journal of General Physiology, 69(4), 497–515.Find this resource:

Hu, L. Y., Ryder, T. R., Rafferty, M. F., Dooley, D. J., Geer, J. J., Lotarski, S. M., … Vartanian, M. G. (1999a). Structure-activity relationship of N-methyl-N-aralkyl-peptidylamines as novel N-type calcium channel blockers. Bioorganic & Medicinal Chemistry Letters, 9(15), 2151–2156.Find this resource:

Hu, L. Y., Ryder, T. R., Rafferty, M. F., Feng, M. R., Lotarski, S. M., Rock, D. M., … Szoke, B. G. (1999b). Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic properties. Journal of Medicinal Chemistry, 42(20), 4239–4249.Find this resource:

Huang, H., Tan, B. Z., Shen, Y., Tao, J., Jiang, F., Sung, Y. Y., … Soong, T. W. (2012). RNA editing of the IQ domain in Ca(v)1.3 channels modulates their Ca²⁺-dependent inactivation. Neuron, 73(2), 304–316.Find this resource:

Huguenard, J. R. (2002). Block of T-type Ca(2+) channels is an important action of succinimide antiabsence drugs. Epilepsy Currents, 2(2), 49–52.Find this resource:

Huguenard, J. R., & Prince, D. A. (1992). A novel T-type current underlies prolonged Ca(2+)-dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 12(10), 3804–3817.Find this resource:

Ikeda, S. R. (1996). Voltage-dependent modulation of N-type calcium channels by G-protein beta gamma subunits. Nature, 380(6571), 255–258.Find this resource:

Jacus, M. O., Uebele, V. N., Renger, J. J., & Todorovic, S. M. (2012). Presynaptic Cav3.2 channels regulate excitatory neurotransmission in nociceptive dorsal horn neurons The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 32(27), 9374–9382.Find this resource:

Jagodic, M. M., Pathirathna, S., Joksovic, P. M., Lee, W., Nelson, M. T., Naik, A. K., … Todorovic, S. M. (2008). Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. Journal of Neurophysiology, 99(6), 3151–3156.Find this resource:

Jagodic, M. M., Pathirathna, S., Nelson, M. T., Mancuso, S., Joksovic, P. M., Rosenberg, E. R., … Todorovic, S. M. (2007). Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 27(12), 3305–3316.Find this resource:

Jarvis, M. F., Scott, V. E., McGaraughty, S., Chu, K. L., Xu, J., Niforatos, W., … Xia, Z. (2014). A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats. Biochemical Pharmacology, 89(4), 536–544.Find this resource:

Joksimovic, S. L., Joksimovic, S. M., Tesic, V., García-Caballero, A., Feseha, S., Zamponi, G. W., … Todorovic, S. M. (2018). Selective inhibition of CaV3.2 channels reverses hyperexcitability of peripheral nociceptors and alleviates postsurgical pain. Science Signaling, 11(545). pii: eaao4425.Find this resource:

Kamp, M. A., Krieger, A., Henry, M., Hescheler, J., Weiergraber, M., & Schneider, T. (2005). Presynaptic “Ca2.3-containing” E-type Ca channels share dual roles during neurotransmitter release. Eur The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 21(6), 1617–1625.Find this resource:

Kang, H. B., Rim, H. K., Park, J. Y., Choi, H. W., Choi, D. L., Seo, J. H., … Lee, J. Y. (2012). In vivo evaluation of oral anti-tumoral effect of 3,4-dihydroquinazoline derivative on solid tumor. Bioorganic & Medicinal Chemistry Letters, 22(2), 1198–1201.Find this resource:

Kang, M. G., & Campbell, K. P. (2003). Gamma subunit of voltage-activated calcium channels. The Journal of Biological Chemistry, 278(24), 21315–21318.Find this resource:

Kang, S. J., Liu, M. G., Shi, T. Y., Zhao, M. G., Kaang, B. K., & Zhuo, M. (2013). N-type voltage gated calcium channels mediate excitatory synaptic transmission in the anterior cingulate cortex of adult mice. Molecular Pain, 9, 58.Find this resource:

Kim, C., Jun, K., Lee, T., Kim, S. S., McEnery, M. W., Chin, H., … Shin, H. S. (2001a). Altered nociceptive response in mice deficient in the alpha(1B) subunit of the voltage-dependent calcium channel. Molecular and Cellular Neurosciences, 18(2), 235–245.Find this resource:

Kim, D., Park, D., Choi, S., Lee, S., Sun, M., Kim, C., & Shin, H. S. (2003). Thalamic control of visceral nociception mediated by T-type Ca2+ channels. Science, 302(5642), 117–119.Find this resource:

Kim, D. S., Yoon, C. H., Lee, S. J., Park, S. Y., Yoo, H. J., & Cho, H. J. (2001). Changes in voltage-gated calcium channel alpha(1) gene expression in rat dorsal root ganglia following peripheral nerve injury. Brain Research. Molecular Brain Research, 96(1–2), 151–156.Find this resource:

Kim, J. H., & Nam, G. (2016) Synthesis and evaluation of 6-pyrazoylamido-3N-substituted azabicyclo[3,1,0]hexane derivatives as T-type calcium channel inhibitors for treatment of neuropathic pain. Bioorganic & Medicinal Chemistry, 24(21), 5028–5035.Find this resource:

Kim, J. H., Keum, G., Chung, H., & Nam, G. (2016). Synthesis and T-type calcium channel-blocking effects of aryl(1,5-disubstituted-pyrazol-3- yl)methyl sulfonamides for neuropathic pain treatment. European Journal of Medicinal Chemistry, 123, 665–672.Find this resource:

King, M. A., Rossi, G. C., Chang, A. H., Williams, L., & Pasternak, G. W. (1997). Spinal analgesic activity of orphanin FQ/nociceptin and its fragments. Neuroscience Letters, 223(2), 113–116.Find this resource:

Kleyman, T. R., & Cragoe, E. J., Jr. (1988). Amiloride and its analogs as tools in the study of ion transport. The Journal of Membrane Biology, 105(1), 1–21.Find this resource:

Klimis, H., Adams, D. J., Callaghan, B., Nevin, S., Alewood, P. F., Vaughan, C. W., … Christie, M. J. (2011). A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain. Pain, 152(2), 259–266.Find this resource:

Klugbauer, N., Marais, E., & Hofmann, F. (2003). Calcium channel alpha2delta subunits: Differential expression, function, and drug binding. Journal of Bioenergetics and Biomembranes, 35(6), 639–647.Find this resource:

Koganei, H., Shoji, M., & Iwata, S. (2009). Suppression of formalin-induced nociception by cilnidipine, a voltage-dependent calcium channel blocker. Biological & Pharmaceutical Bulletin, 32(10), 1695–1700.Find this resource:

Kondo, I., Marvizon, J. C., Song, B., Salgado, F., Codeluppi, S., Hua, X. Y., & Yaksh, T. L. (2005). Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 25(14), 3651–3660.Find this resource:

Koschak, A., Reimer, D., Walter, D., Hoda, J. C., Heinzle, T., Grabner, M., & Striessnig, J. (2003). Cav1.4alpha1 subunits can form slowly inactivating dihydropyridine-sensitive L-type Ca2+ channels lacking Ca2+-dependent inactivation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23(14), 6041–6049.Find this resource:

Kuraishi, Y., Yamaguchi, T., & Miyamoto, T. (2000). Itch-scratch responses induced by opioids through central mu opioid receptors in mice. Journal of Biomedical Science, 7(3), 248–252.Find this resource:

Lana, B., Schlick, B., Martin, S., Pratt, W. S., Page, K. M., Goncalves, L., … Dolphin, A. C. (2014). Differential upregulation in DRG neurons of an α2δ-1 splice variant with a lower affinity for gabapentin after peripheral sensory nerve injury. Pain, 155(3), 522–533.Find this resource:

Lee, J. H., Gomora, J. C., Cribbs, L. L., & Perez-Reyes, E. (1999). Nickel block of three cloned T-type calcium channels: Low concentrations selectively block alpha1H. Biophysical Journal, 77(6), 3034–3042.Find this resource:

Lee, M. (2014). Z944: A first in class T-type calcium channel modulator for the treatment of pain. Journal of the Peripheral Nervous System, Suppl. 2, S11–S12.Find this resource:

Lee, S., Kim, Y., Back, S. K., Choi, H. W., Lee, J. Y., Jung, H. H., … Kim, J. I. (2010). Analgesic effect of highly reversible ω-conotoxin FVIA on N type Ca2+ channels. Molecular Pain, 6:97.Find this resource:

Lewis, R. J., Nielsen, K. J., Craik, D. J., Loughnan, M. L., Adams, D. A., Sharpe, I. A., … Alewood, P. F. (2000). Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. The Journal of Biological Chemistry, 275(45), 35335–35344.Find this resource:

Li, C. Y., Zhang, X. L., Matthews, E. A., Li, K. W., Kurwa, A., Boroujerdi, A., … Luo, Z. D. (2001). Calcium channel alpha2delta1 subunit mediates spinal hyperexcitability in pain modulation. Pain, 125(1–2), 20–34.Find this resource:

Li, C.Y., Zhang, X.L., Matthews, E.A., Li, K.W., Kurwa, A., Boroujerdi, A., … Luo ZD. (2006) Calcium channel alpha2delta1 subunit mediates spinal hyperexcitability in pain modulation. Pain 125(1), 20–34.Find this resource:

Li, K. W., Yu, Y. P., Zhou, C., Kim, D. S., Lin, B., Sharp, K., … Luo, Z. D. (2014). Calcium channel α2δ1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis. The Journal of Biological Chemistry, 289(10), 7025–7037.Find this resource:

Li, Y., Tatsui, C. E., Rhines, L. D., North, R. Y., Harrison, D. S., Cassidy, R. M., … Dougherty, P. M. (2017). Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy. Pain, 158(3), 417–429.Find this resource:

Lipscombe, D., Andrade, A., & Allen, S. E. (2013). Alternative splicing: Functional diversity among voltage-gated calcium channels and behavioral consequences. Biochimica et Biophysica Acta, 1828(7), 1522–1529.Find this resource:

Lirk, P., Poroli, M., Rigaud, M., Fuchs, A., Fillip, P., Huang, C. Y., … Hogan, Q. (2008). Modulators of calcium influx regulate membrane excitability in rat dorsal root ganglion neurons. Anesthesia and Analgesia, 107(2), 673–685.Find this resource:

Liu, H., Felix, R., Gurnett, C. A., De Waard, M., Witcher, D. R., & Campbell, K. P. (1996). Expression and subunit interaction of voltage-dependent Ca2+ channels in PC12 cells. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 16(23), 7557–7565.Find this resource:

Liu, M. G., Kang, S. J., Shi, T. Y., Koga, K., Zhang, M. M., Collingridge, G. L., … Zhuo, M. (2013). Long-term potentiation of synaptic transmission in the adult mouse insular cortex: Multielectrode array recordings. Journal of Neurophysiology, 110(2), 505–521.Find this resource:

Liu, X. Y., Liu, Z. C., Sun, Y. G., Ross, M., Kim, S., Tsai, F. F., … Chen, Z. F. (2011). Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell, 147(2), 447–458.Find this resource:

Lopez-Charcas, O., Rivera, M., & Gomora, J. C. (2012). Block of human CaV3 channels by the diuretic amiloride. Molecular Pharmacology, 82(4), 658–667.Find this resource:

Lotarski, S., Hain, H., Peterson, J., Galvin, S., Strenkowski, B., Donevan, S., & Offord, J. (2014). Anticonvulsant activity of pregabalin in the maximal electroshock-induced seizure assay in α2δ1 (R217A) and α2δ2 (R279A) mouse mutants. Epilepsy Research, 108(5), 833–842.Find this resource:

Lu, Z., Xu, J., Xu, M., Rossi, G. C., Majumdar, S., Pasternak, G. W., & Pan, Y. X. (2018). Truncated μ-opioid receptors with six transmembrane domains are essential for opioid analgesia. Anesthesia and Analgesia, 126(3), 1050–1057.Find this resource:

Luo, Z. D., Calcutt, N. A., Higuera, E. S., Valder, C. R., Song, Y. H., Svensson, C. I., & Myers, R. R. (2002). Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. The Journal of Pharmacology and Experimental Therapeutics, 303(3), 1199–1205.Find this resource:

Luo, Z. D., Chaplan, S. R., Higuera, E. S., Sorkin, L. S., Stauderman, K. A., Williams, M. E., & Yaksh, T. L. (2001). Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 21(6), 1868–1875.Find this resource:

Manev, H., Bertolino, M., & DeErausquin, G. (1990). Amiloride blocks glutamate-operated cationic channels and protects neurons in culture from glutamate-induced death. Neuropharmacology, 29(12), 1103–1110.Find this resource:

Marger, F., Gelot, A., Alloui, A., Matricon, J., Ferrer, J. F., Barrère, C., … Ardid, D. (2011). T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome. Proceedings of the National Academy of Sciences of the United States of America, 108, 11268–11273.Find this resource:

Marrone, G. F., Grinnell, S. G., Lu, Z., Rossi, G. C., Le Rouzic, V., Xu, J., … Pasternak, G. W. (2016). Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS. Proceedings of the National Academy of Sciences of the United States of America, 113(13), 3663–3668.Find this resource:

Matthews, E. A., Bee, L. A., Stephens, G. J., & Dickenson, A. H. (2007). The Cav2.3 calcium channel antagonist SNX-482 reduces dorsal horn neuronal responses in a rat model of chronic neuropathic pain. European Journal of Neuroscience, 25(12), 3561–3569.Find this resource:

McCormick, D. A., & Huguenard, J. R. (1992) A model of the electrophysiological properties of thalamocortical relay neurons. Journal of Neurophysiology, 68(4): 1384–1400.Find this resource:

McDonald, J., & Lambert, D. G. (2005). Opioid receptors. Continuing Education in Anaesthesia, Critical Care, & Pain, 5(1), 22–25.Find this resource:

McKay, B. E., McRory, J. E., Molineux, M. L., Hamid, J., Snutch, T. P., Zamponi, G. W., & Turner, R. W. (2006). Ca(V)3 T-type calcium channel isoforms differentially distribute to somatic and dendritic compartments in rat central neurons. European Journal of Neuroscience, (9), 2581–2594.Find this resource:

M’Dahoma, S., Gadotti, V. M., Zhang, F. X., Park, B., Nam, J. H., Onnis, V., … Zamponi, G. W. (2016). Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain. Pflugers Archiv: European Journal of Physiology, 468(2), 193–199.Find this resource:

Messinger, R. B., Naik, A. K., Jagodic, M. M., Nelson, M. T., Lee, W. Y., Choe, W. J., … Jevtovic-Todorovic, V. (2009). In vivo silencing of the Ca(V)3.2 T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocin-induced diabetic neuropathy. Pain, 145(1–2), 184–195.Find this resource:

Mika, J., Przewłocki, R., & Przewłocka, B. (2001). The role of delta-opioid receptor subtypes in neuropathic pain. European Journal of Pharmacology, 415(1), 31–37.Find this resource:

Mikami, A., Imoto, K., Tanabe, T., Niidome, T., Mori, Y., Takeshima, H., … Numa, S. (1989). Primary structure and functional expression of the cardiac dihydropyridine-sensitive calcium channel. Nature, 340(6230), 230–233.Find this resource:

Miljanich, G. P. (2004). Ziconotide: Neuronal calcium channel blocker for treating severe chronic pain. Current Medicinal Chemistry, 11(23), 3029–3040.Find this resource:

Mishra SK, Hermsmeyer K (1994). Resting state block and use independence of rat vascular muscle Ca++ channels by Ro 40–5967. The Journal of Pharmacology and Experimental Therapeutics, 269(1), 178–183.Find this resource:

Mizoguchi, H., Watanabe, C., Sakurada, T., & Sakurada, S. (2012). New vistas in opioid control of pain. Current Opinion in Pharmacology, 12(1), 87–91.Find this resource:

Moises, H. C., Rusin, K. I., & Macdonald, R. L. (1994). Mu- and kappa-opioid receptors selectively reduce the same transient components of high-threshold calcium current in rat dorsal root ganglion sensory neurons. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 14(10), 5903–5916.Find this resource:

Mori, Y., Friedrich, T., Kim, M. S., Mikami, A., Nakai, J., Ruth, P., … Numa, S. (1991). Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature, 350(6317), 398–402.Find this resource:

Morikawa, H., Fukuda, K., Mima, H., Shoda, T., Kato, S., & Mori, K. (1998). Desensitization and resensitization of delta-opioid receptor-mediated Ca2+ channel inhibition in NG108-15 cells. British Journal of Pharmacology, 123(6), 1111–1118.Find this resource:

Motin, L., Yasuda, T., Schroeder, C. I., Lewis, R. J., & Adams, D. J. (2007). Omega-conotoxin CVIB differentially inhibits native and recombinant N- and P/Q-type calcium channels. European Journal of Neuroscience, 25(2), 435–444.Find this resource:

Motin, L. G., Bennett, M. R., & Christie, M. J. (1995). Opioids acting on delta-receptors modulate Ca2+ currents in cultured postganglionic neurones of avian ciliary ganglia. Neuroscience Letters, 193(1), 21–24.Find this resource:

Moutal, A., Dustrude, E. T., Largent-Milnes, T. M., Vanderah, T. W., Khanna, M., & Khanna, R. (2017). Blocking CRMP2 SUMOylation reverses neuropathic pain. Molecular Psychiatry, 23(11), 2119–2121. doi: 10.1038/mp.2017.117Find this resource:

Mullins, M. E., Horowitz, B. Z., Linden, D. H., Smith, G. W., Norton, R. L., & Stump, J. (1998). Life threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers. JAMA, 280(2), 157–158.Find this resource:

Myoga, M. H., & Regehr, W. G. (2011). Calcium microdomains near R-type calcium channels control the induction of presynaptic long-term potentiation at parallel fiber to purkinje cell synapses. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 31, 5235–5243.Find this resource:

Nelson, M. T., Joksovic, P. M., Perez-Reyes, E., & Todorovic, S. M. (2005). The endogenous redox agent L-cysteine induces T-type Ca2+ channel-dependent sensitization of a novel subpopulation of rat peripheral nociceptors. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 25(38), 8766–8775.Find this resource:

Nozaki, C., Le Bourdonnec, B., Reiss, D., Windh, R. T., Little, P. J., Dolle, R. E., … Gavériaux-Ruff, C. (2012). δ-Opioid mechanisms for ADL5747 and ADL5859 effects in mice: Analgesia, locomotion, and receptor internalization. The Journal of Pharmacology and Experimental Therapeutics, 342(3), 799–807.Find this resource:

Ohkubo, T., Yamazaki, J., & Kitamura, K. (2010). Tarantula toxin ProTx-I differentiates between human T-type voltage-gated Ca2+ channels Cav3.1 and Cav3.2. Journal of Pharmacological Sciences, 112(4), 452–458.Find this resource:

Olamendi-Portugal, T., García, B. I., López-González, I., Van Der Walt, J., Dyason, K., Ulens, C., … Possani, L. D. (2002). Two new scorpion toxins that target voltage-gated Ca2+ and Na+ channels. Biochemical and Biophysical Research Communications, 299(4), 562–568.Find this resource:

Olivera, B. M., McIntosh, J. M., Cruz, L. J., Luque, F. A., & Gray, W. R. (1984). Purification and sequence of a presynaptic peptide toxin from Conus geographus venom. Biochemistry, 23(22), 5087–5090.Find this resource:

Orestes, P., Bojadzic, D., Lee, J., Leach, E., Salajegheh, R., Digruccio, M. R., … Todorovic, S. M. (2011). Free radical signalling underlies inhibition of CaV3.2 T-type calcium channels by nitrous oxide in the pain pathway. The Journal of Physiology, 589(Pt. 1), 135–148.Find this resource:

Orestes, P., Osuru, H. P., McIntire, W. E., Jacus, M. O., Salajegheh, R., Jagodic, M. M., … Todorovic, S. M. (2013). Reversal of neuropathic pain in diabetes by targeting glycosylation of Ca(V)3.2 T-type calcium channels. Diabetes 62(11), 3828–3838.Find this resource:

Page, K. M., Rothwell, S. W., & Dolphin, A. C. (2016). The CaVβ subunit protects the I–II loop of the voltage-gated calcium channel CaV2.2 from proteasomal degradation but not oligoubiquitination. The Journal of Biological Chemistry, 291(39), 20402–20416.Find this resource:

Pajouhesh, H., Feng, Z. P., Ding, Y., Zhang, L., Pajouhesh, H., Morrison, J. L., … Snutch, T. P. (2010). Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors. Bioorganic & Medicinal Chemistry Letters, 20(4), 1378–1383.Find this resource:

Pajouhesh, H., Feng, Z. P., Zhang, L., Pajouhesh, H., Jiang, X., Hendricson, A., … Snutch, T. P. (2012). Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors. Bioorganic & Medicinal Chemistry Letters, 22(12), 4153–4158.Find this resource:

Park, J. Y., Remy, S., Varela, J., Cooper, D. C., Chung, S., Kang, H. W., … Spruston, N. (2010). A post-burst after depolarization is mediated by group I metabotropic glutamate receptor-dependent upregulation of Ca(v)2.3 R-type calcium channels in CA1 pyramidal neurons. PLoS Biology, 8, e1000534.Find this resource:

Patel, R., & Dickenson, A. H. (2016). Mechanisms of the gabapentinoids and α2δ-1 calcium channel subunit in neuropathic pain. Pharmacology Research & Perspectives, 4(2), e00205.Find this resource:

Patil, P. G., de Leon, M., Reed, R. R., Dubel, S., Snutch, T. P., & Yue, D. T. (1996). Elementary events underlying voltage-dependent G-protein inhibition of N-type calcium channels. Biophysical Journal, 71(5), 2509–2521.Find this resource:

Penn, R. D., & Paice, J. A. (2000). Adverse effects associated with the intrathecal administration of ziconotide. Pain, 85(1–2), 291–296.Find this resource:

Perez-Reyes, E. (2003). Molecular physiology of low-voltage-activated t-type calcium channels. Physiological Reviews, 83(1), 117–161.Find this resource:

Perez-Reyes, E., Cribbs, L. L., Daud, A., Lacerda, A. E., Barclay, J., Williamson, M. P., … Lee, J. H. (1998). Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature, 391(6670), 896–900.Find this resource:

Pietrobon, D., & Moskowitz, M. A. (2017). Pathophysiology of migraine. Annual Review of Physiology, 75, 365–391.Find this resource:

Piltonen, M., Parisien, M., Grégoire, S., Chabot-Doré, A. J., Jafarnejad, S. M., Bérubé, P., … Diatchenko, L. (2018). Alternative splicing of the delta-opioid receptor gene suggests existence of new functional isoforms. Molecular Neurobiology. doi:10.1007/s12035-018-1253-zFind this resource:

Pragnell, M., De Waard, M., Mori, Y., Tanabe, T., Snutch, T. P., Campbell, K. P. (1994). Calcium channel beta-subunit binds to a conserved motif in the I–II cytoplasmic linker of the alpha 1-subunit. Nature, 368(6466), 67–70.Find this resource:

Qin, N., Olcese, R., Stefani, E., & Birnbaumer, L. (1998). Modulation of human neuronal alpha 1E-type calcium channel by alpha 2 delta-subunit. American Journal of Physiology, 274(5, Pt. 1), C1324–C1331.Find this resource:

Quintero, J. E., Dooley, D. J., Pomerleau, F., Huettl, P., & Gerhardt, G. A. (2011). Amperometric measurement of glutamate release modulation by gabapentin and pregabalin in rat neocortical slices: Role of voltage-sensitive Ca2+ α2δ-1 subunit. The Journal of Pharmacology and Experimental Therapeutics, 338(1), 240–245.Find this resource:

Radwani, H., Lopez-Gonzalez, M. J., Cattaert, D., Roca-Lapirot, O., Dobremez, E., Bouali-Benazzouz, R., … Fossat, P. (2016). Cav1.2 and Cav1.3 L-type calcium channels independently control short- and long-term sensitization to pain. The Journal of Physiology, 594(22), 6607–6626.Find this resource:

Ragsdale, D. S., Scheuer, T., & Catterall, W. A. (1991). Frequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anesthetic, antiarrhythmic, and anticonvulsant drugs. Molecular Pharmacology, 40(5), 756–765.Find this resource:

Raingo, J., Castiglioni, A. J., & Lipscombe, D. (2007). Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors. Nature Neuroscience, 10(3), 285–292.Find this resource:

Rauck, R. L., Wallace, M. S., Burton, A. W., Kapural, L., &North, J. M. (2009). Intrathecal ziconotide for neuropathic pain: A review. Pain Practice: The Official Journal of the World Institute of Pain, 9(5), 327–337.Find this resource:

Ripsch, M. S., Ballard, C. J., Khanna, M., Hurley, J. H., White, F. A., & Khanna, R. (2012). A peptide uncoupling CRMP-2 from the presynaptic Ca2 channel complex demonstrates efficacy in animal models of migraine and aids therapy-induced neuropathy. Translational Neuroscience, 3(1), 1–8.Find this resource:

Rock, D. M., Kelly, K. M., & Macdonald, R. L. (1993). Gabapentin actions on ligand- and voltage-gated responses in cultured rodent neurons. Epilepsy Research 16(2), 89–98.Find this resource:

Rosenberg, J. M., Harrell, C., Ristic, H., Werner, R. A., & de Rosayro, A. M. (1997). The effect of gabapentin on neuropathic pain. The Clinical Journal of Pain, 13(3), 251–255.Find this resource:

Ryder, T. R., Hu, L. Y., Rafferty, M. F., Lotarski, S. M., Rock, D. M., Stoehr, S. J., … Szoke, B. G. (2000). Structure-activity relationship at the leucine side chain in a series of N,N-dialkyldipeptidyl-amines as N-type calcium channel blockers. Drug Design and Discovery, 16(4), 317–322.Find this resource:

Saegusa, H., Kurihara, T., Zong, S., Kazuno, A., Matsuda, Y., Nonaka, T., … Tanabe, T. (2001). Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel. The EMBO Journal, 20(10), 2349–2356.Find this resource:

Saegusa, H., Kurihara, T., Zong, S., Minowa, O., Kazuno, A., Han, W. M., … Tanabe, T. (2000). Altered pain responses in mice lacking alpha 1E subunit of the voltage-dependent Ca2 channel. Proceedings of the National Academy of Sciences of the United States of America, 97(11), 6132–6137.Find this resource:

Saegusa, H., Matsuda, Y., & Tanabe, T. (2002). Effects of ablation of N- and R-type Ca(2+) channels on pain transmission. Neuroscience Research, 43(1), 1–7.Find this resource:

Santi, C. M., Cayabyab, F. S., Sutton, K. G., McRory, J. E., Mezeyova, J., Hamming, K. S., … Snutch, T. P. (2002). Differential inhibition of T-type calcium channels by neuroleptics. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 22(2), 396–403.Find this resource:

Satoh, M., Kubota, A., Iwama, T., Wada, T., Yasui, M., Fujibayashi, K., & Takagi, H. (1983). Comparison of analgesic potencies of mu, delta and kappa agonists locally applied to various CNS regions relevant to analgesia in rats. Life Sciences, 33(Suppl, 1), 689–692.Find this resource:

Scherrer, G., Imamachi, N., Cao, Y. Q., Contet, C., Mennicken, F., O’Donnell, D., … Basbaum, A. I. (2009). Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell, 137(6), 1148–1159.Find this resource:

Schmalhofer, W. A., Calhoun, J., Burrows, R., Bailey, T., Kohler, M. G., Weinglass, A. B., … Priest, B. T. (2008). ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Molecular Pharmacology, 74(5), 1476–1484.Find this resource:

Schroeder, C. I., Doering, C. J., Zamponi, G. W., & Lewis, R. J. (2006). N-type calcium channel blockers: Novel therapeutics for the treatment of pain. Medicinal Chemistry, 2(5), 535–543.Find this resource:

Schuele, S. U., Kellinghaus, C., Shook, S. J., Boulis, N., Bethoux, F. A., & Loddenkemper, T. (2005). Incidence of seizures in patients with multiple sclerosis treated with intrathecal baclofen. Neurology, 64(6), 1086–1087.Find this resource:

Scott, D. A., Wright, C. E., & Angus, J. A. (2002). Actions of intrathecal omega-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. European Journal of Pharmacology, 451(3), 279–286.Find this resource:

Sekiguchi, F., Kawara, Y., Tsubota, M., Kawakami, E., Ozaki, T., Kawaishi, Y., … Kawabata, A. (2016). Therapeutic potential of RQ-00311651, a novel T-type Ca2+ channel blocker, in distinct rodent models for neuropathic and visceral pain. Pain, 157(8), 1655–1665.Find this resource:

Serra, J., Duan, W. R., Locke, C., Solà, R., Liu, W., & Nothaft, W. (2015). Effects of a T-type calcium channel blocker, ABT-639, on spontaneous activity in C-nociceptors in patients with painful diabetic neuropathy: A randomized controlled trial. Pain, 156(11), 2175–2183.Find this resource:

Shen, F. Y., Chen, Z. Y., Zhong, W., Ma, L. Q., Chen, C., Yang, Z. J., … Wang, Y. W. (2015). Alleviation of neuropathic pain by regulating T-type calcium channels in rat anterior cingulate cortex. Molecular Pain, 11, 7.Find this resource:

Sidach, S. S., & Mintz, I. M. (2002). Kurtoxin, a gating modifier of neuronal high- and low-threshold Ca channels. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 22(6), 2023–2034.Find this resource:

Silva, R. B., Sperotto, N. D., Andrade, E. L., Pereira, T. C., Leite, C. E., de Souza, A. H., … Campos, M. M. (2015). Spinal blockage of P/Q- or N-type voltage-gated calcium channels modulates functional and symptomatic changes related to haemorrhagic cystitis in mice. British Journal of Pharmacology, 172(3), 924–939.Find this resource:

Simms, B. A., & Zamponi, G. W. (2014). Neuronal voltage-gated calcium channels: Structure, function, and dysfunction. Neuron, 82(1), 24–45.Find this resource:

Smith, M. T., Cabot, P. J., Ross, F. B., Robertson, A. D., & Lewis, R. J. (2002). The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain, 96(1–2), 119–127.Find this resource:

Snutch, T.P. (2005). Targeting chronic and neuropathic pain: The N-type calcium channel comes of age. NeuroRx: The Journal of the American Society for Experimental NeuroTherapeutics, 2, 662–670.Find this resource:

Snutch, T. P., & Baillie, D. L.. (1997a). US Patent No. 7,157,243B1. Washington, DC: US Patent and Trademark Office.Find this resource:

Snutch, T. P., & Baillie, D. L. (1997b). US Patent No. 7,297,504B1. Washington, DC: US Patent and Trademark Office.Find this resource:

Snutch, T. P., & David, L. S. (2006). T-type calcium channels: An emerging therapeutic target for the treatment of pain. Drug Development Research, 67, 404–415.Find this resource:

Snutch T. P., Leonard, J. P., Gilbert, M. M., Lester, & Davidson, N. (1990). Rat brain expresses a heterogeneous family of calcium channels. Proceedings of the National Academy if Sciences of the United States of America, 87, 3391–3395.Find this resource:

Snutch, T. P., & Zamponi, G. W. (2018). Recent advances in the development of T-type calcium channel blockers for pain intervention British Journal of Pharmacology, 175(12), 2375–2383.Find this resource:

Soong, T. W., Stea, A., Hodson, C. D., Dubel, S. J., Vincent, S. R., & Snutch, T. P. (1993). Structure and functional expression of a member of the low voltage-activated calcium channel family. Science, 260(5111), 1133–1136.Find this resource:

Spahn, V., & Stein, C. (2017). Targeting delta opioid receptors for pain treatment: Drugs in phase I and II clinical development. Expert Opinion on Investigational Drugs, 26(2), 155–160.Find this resource:

Staats, P. S., Yearwood, T., Charapata, S. G., Presley, R. W., Wallace, M. S., Byas-Smith, M., … Ellis, D. (2004). Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: A randomized controlled trial. JAMA, 291(1), 63–70.Find this resource:

Starr, T. V. B., Prystay, W., & Snutch, T. P. (1991). Primary structure of a calcium channel that is highly expressed in the rat cerebellum. Proceedings of the National Academy of Sciences of the United States of America, 88, 5621–5625.Find this resource:

Stemkowski, P., García-Caballero, A., Gadotti, V. M., M’Dahoma, S., Huang, S., Black, S. A., … Zamponi, G. W. (2016). TRPV1 nociceptor activity initiates USP5/Ttype channel-mediated plasticity. Cell Reports, 17(11), 2901–2912.Find this resource:

Suzuki, R., Rahman, W., Rygh, L. J., Webber, M., Hunt, S. P., & Dickenson, A. H. (2005). Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin. Pain, 117(3), 292–303.Find this resource:

Swayne, L. A, & Bourinet, E. (2008). Voltage-gated calcium channels in chronic pain: Emerging role of alternative splicing. Pflugers Archiv: European Journal of Physiology, 456(3), 459–466.Find this resource:

Swensen, A. M., Herrington, J., Bugianesi, R. M., Dai, G., Haedo, R. J., Ratliff, K. S., … McManus, O. B. (2012). Characterization of the substituted N-triazole oxindole TROX-1, a small-molecule, state-dependent inhibitor of Ca(V)2 calcium channels. Molecular Pharmacology, 81(3), 488–497.Find this resource:

Takahashi, M., Seagar, M. J., Jones, J. F., Reber, B. F., & Catterall, W. A. (1987). Subunit structure of dihydropyridine-sensitive calcium channels from skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America, 84(15), 5478–5482.Find this resource:

Takasu, K., Ono, H., & Tanabe, M. (2008). Gabapentin produces PKA-dependent pre-synaptic inhibition of GABAergic synaptic transmission in LC neurons following partial nerve injury in mice. Journal of Neurochemistry, 105(3), 933–942.Find this resource:

Tanabe, M., Takasu, K., Kasuya, N., Shimizu, S., Honda, M., & Ono, H. (2005). Role of descending noradrenergic system and spinal alpha2-adrenergic receptors in the effects of gabapentin on thermal and mechanical nociception after partial nerve injury in the mouse. British Journal of Pharmacology, 144(5), 703–714.Find this resource:

Tanabe, T., Takeshima, H., Mikami, A., Flockerzi, V., Takahashi, H., Kangawa, K., … Numa, S. (1987). Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature, 328(6128), 313–318.Find this resource:

Tedford, H. W., & Zamponi, G. W. (2006). Direct G protein modulation of Cav2 calcium channels. Pharmacological Reviews, 58(4), 837–862.Find this resource:

Terrence, C. F., Fromm, G. H., & Tenicela, R. (1985). Baclofen as an analgesic in chronic peripheral nerve disease. European Neurology, 24(6), 380–385.Find this resource:

Thompson, J. C., Dunbar, E., & Laye, R. R. (2006). Treatment challenges and complications with ziconotide monotherapy in established pump patients. Pain Physician, 9(2), 147–152.Find this resource:

Todorovic, S. M., & Jevtovic-Todorovic, V. (2013). Neuropathic pain: Role for presynaptic T-type channels in nociceptive signaling. Pflugers Archiv: European Journal of Physiology, 465(7), 921–927.Find this resource:

Tomlinson, W. J., Stea, A., Bourinet, E., Charnet, P., Nargeot, J., & Snutch, T. P. (1993). Functional properties of a neuronal class C L-type calcium channel. Neuropharmacology, 32(11), 1117–1126.Find this resource:

Toselli, M., Tosetti, P., & Taglietti, V. (1999). Kinetic study of N-type calcium current modulation by delta-opioid receptor activation in the mammalian cell line NG108-15. Biophysical Journal, 76(5), 2560–2574.Find this resource:

Tran-Van-Minh, A., & Dolphin, A. C. (2010). The alpha2delta ligand gabapentin inhibits the Rab11-dependent recycling of the calcium channel subunit alpha2delta-2. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30(38), 12856–12867.Find this resource:

Tringham, E., Powell, K. L., Cain, S. M., Kuplast, K., Mezeyova, J., Weerapura, M., … Snutch, T. P. (2012). T-type calcium channel blockers that attenuate halamic burst firing and suppress absence seizures. Science Translational Medicine, 4, 121ra19.Find this resource:

Tuluc, P., Kern, G., Obermair, G. J., & Flucher, B. E. (2007). Computer modeling of siRNA knockdown effects indicates an essential role of the Ca2+ channel alpha2delta-1 subunit in cardiac excitation-contraction coupling. Proceedings of the National Academy of Sciences of the United States of America, 104(26), 11091–11096.Find this resource:

Van den Maagdenberg, A. M., Pizzorusso, T., Kaja, S., Terpolilli, N., Shapovalova, M., Hoebeek, F. E., … Ferrari, M. D. (2010). High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Annals of Neurology, 67(1), 85–98.Find this resource:

Varrassi, G., Fusco, M., Skaper, S. D., Battelli, D., Zis, P., Coaccioli, S., … Paladini, A. (2018). A pharmacological rationale to reduce the incidence of opioid induced tolerance and hyperalgesia: A review. Pain and Therapy, 7(1), 59–75.Find this resource:

Ver Donck, A., Collins, R., Rauck, R. L., & Nitescu, P. (2008). An Open-Label, Multicenter Study of the Safety and Efficacy of Intrathecal Ziconotide for Severe Chronic Pain When Delivered via an External Pump. Neuromodulation, 11(2), 103–111.Find this resource:

Waithe, D., Ferron, L., Page, K. M., Chaggar, K., & Dolphin, A. C. (2011). Beta-subunits promote the expression of Ca(V)2.2 channels by reducing their proteasomal degradation. The Journal of Biological Chemistry, 286(11), 9598–9611.Find this resource:

Wakamori, M., Mikala, G., & Mori, Y. (1999). Auxiliary subunits operate as a molecular switch in determining gating behaviour of the unitary N-type Ca2+ channel current in Xenopus oocytes. The Journal of Physiology, 15(517, Pt. 3), 659–672.Find this resource:

Wallace, M., Duan, R., Liu, W., Locke, C., & Nothaft, W. (2016). A randomized, double-blind, placebo-controlled, crossover study of the T-type calcium channel blocker ABT-639 in an intradermal capsaicin experimental pain model in healthy adults. Pain Medicine, 17(3), 551–560.Find this resource:

Wallace, M. S., Charapata, S. G., Fisher, R., Byas-Smith, M., Staats, P. S., Mayo, M., … Ziconotide Nonmalignant Pain Study Group. (2006). Intrathecal ziconotide in the treatment of chronic nonmalignant pain: A randomized, double-blind, placebo-controlled clinical trial. Neuromodulation, 9(2), 75–86.Find this resource:

Wang, H., Sun, H., Della Penna, K., Benz, R. J., Xu, J., Gerhold, D. L., … Koblan, K. S. (2002). Chronic neuropathic pain is accompanied by global changes in gene expression and shares pathobiology with neurodegenerative diseases. Neuroscience, 114(3), 529–546.Find this resource:

Wang, Y. X., Pettus, M., Gao, D., Phillips, C., & Scott Bowersox, S. (2000). Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain. Pain, 84(2–3), 151–158.Find this resource:

Waxmann, S. G., & Zamponi, G. W. (2014). Regulating excitability of peripheral afferents: Emerging ion channel targets. Nature Neuroscience, 17(2), 153–163.Find this resource:

Weiss, N., Black, S. A., Bladen, C., Chen, L., & Zamponi, G. W. (2013). Surface expression and function of Cav3.2 T-type calcium channels are controlled by asparagine-linked glycosylation. Pflugers Archiv: European Journal of Physiology, 465(8), 1159–1170.Find this resource:

Wen, X. J., Xu, S. Y., Chen, Z. X., Yang, C. X., Liang, H., & Li, H. (2010). The roles of T-type calcium channel in the development of neuropathic pain following chronic compression of rat dorsal root ganglia. Pharmacology, 85(5), 295–300.Find this resource:

Westenbroek, R. E., Hell, J. W., Warner, C., Dubel, S. J., Snutch, T. P., & Catterall, W. A. (1992). Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. Neuron, 9(6), 1099–1115.Find this resource:

Westenbroek, R. E., Sakurai, T., Elliott, E. M., Hell, J. W., Starr, T. V., Snutch, T. P., & Catterall, W. A. (1995). Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 15(10), 6403–6418.Find this resource:

Wheeler, D. G., Groth, R. D., Ma, H., Barrett, C. F., Owen, S. F., Safa, P., & Tsien, R. W. (2012). CaV1 and CaV2 channels engage distinct modes of Ca2+ signaling to control CREB-dependent gene expression. Cell, 149(5), 1112–1124.Find this resource:

Williams, M. E., Brust, P. F., Feldman, D. H., Patthi, S., Simerson, S., Maroufi, A., … Harpold, M. M. (1992). Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel. Science, 257(5068), 389–395.Find this resource:

Willow, M., Gonoi, T., & Catterall, W. A. (1985). Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Molecular Pharmacology, 27(5), 549–558.Find this resource:

Wilson, S. M., Schmutzler, B. S., Brittain, J. M., Dustrude, E. T., Ripsch, M. S., Pellman, J. J., … Khanna, R. (2012). Inhibition of transmitter release and attenuation of anti-retroviral-associated and tibial nerve injury-related painful peripheral neuropathy by novel synthetic Ca2+ channel peptides. The Journal of Biological Chemistry, 287(42), 35065–35077.Find this resource:

Witcher, D. R., De Waard, M., Sakamoto, J., Franzini-Armstrong, C., Pragnell, M., Kahl, S. D., & Campbell, K. P. (1993). Subunit identification and reconstitution of the N-type Ca2+ channel complex purified from brain. Science, 261(5120), 486–489.Find this resource:

Wu, J., Yan, Z., Li, Z., Qian, X., Lu, S., Dong, M., … Yan, N. (2016). Structure of the voltage-gated calcium channel Ca(v)1.1 at 3.6 Å resolution. Nature, 537(7619), 191–196.Find this resource:

Wu, L. G., Borst, J. G., & Sakmann, B. (1998). R-type Ca2 currents evoke transmitter release at a rat central synapse. Proceedings of the National Academy of Sciences of the United States of America, 95(8), 4720–4725.Find this resource:

Xiao, W., Boroujerdi, A., Bennett, G. J., & Luo, Z. D. (2007). Chemotherapy-evoked painful peripheral neuropathy: Analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit. Neuroscience, 144(2), 714–720.Find this resource:

Yang, J., Xie, M. X., Hu, L., Wang, X. F., Mai, J. Z., Li, Y. Y., … Liu, X. G. (2018). Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury. Brain, Behavior, and Immunity, 71, 52–65.Find this resource:

Yang, L., & Stephens, G. J. (2009). Effects of neuropathy on high-voltage-activated Ca(2+) current in sensory neurons. Cell Calcium, 46(4), 248–256.Find this resource:

Yasuda, T., Chen, L., Barr, W., McRory, J. E., Lewis, R. J., Adams, D. J., & Zamponi, G. W. (2004). Auxiliary subunit regulation of high-voltage activated calcium channels expressed in mammalian cells. European Journal of Neuroscience, 20(1), 1–13.Find this resource:

Yeon, K. Y., Sim, M. Y., Choi, S. Y., Lee, S. J., Park, K., Kim, J. S., … Oh, S. B. (2004). Molecular mechanisms underlying calcium current modulation by nociception. Neuroreport, 15(14), 2205–2209.Find this resource:

You, H., Gadotti, V. M., Petrov, R. R., Zamponi, G. W., & Diaz, P. (2011). Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands. Molecular Pain, 7, 89.Find this resource:

Yu, Y. P., Gong, N., Kweon, T. D., Vo, B., & Luo, Z. D. (2018). Gabapentin prevents synaptogenesis between sensory and spinal cord neurons induced by thrombospondin-4 acting on pre-synaptic Cav α2 δ1 subunits and involving T-type Ca2+ channels. British Journal of Pharmacology, 175(12), 2348–2361.Find this resource:

Zaman, T., Lee, K., Park, C., Paydar, A., Choi, J. H., Cheong, E., … Shin, H. S. (2011). Cav2.3 channels are critical for oscillatory burst discharges in the reticular thalamus and absence epilepsy. Neuron, 70, 95–108.Find this resource:

Zamponi, G. W., Bourinet, E., Nelson, D., Nargeot, J., & Snutch, T. P. (1997). Crosstalk between G proteins and protein kinase C mediated by the calcium channel alpha1 subunit. Nature, 385(6615), 442–446.Find this resource:

Zamponi, G. W., Bourinet, E., & Snutch, T. P. (1996). Nickel block of a family of neuronal calcium channels: Subtype- and subunit-dependent action at multiple sites. The Journal of Membrane Biology, 151(1), 77–90.Find this resource:

Zamponi, G. W., Feng, Z. P., Zhang, L., Pajouhesh, H., Ding, Y., Belardetti, F., … Snutch, T. P. (2009). Scaffold-based design and synthesis of potent N-type calcium channel blockers. Bioorganic & Medicinal Chemistry Letters, 19(22), 6467–6472.Find this resource:

Zamponi, G. W., Striessnig, J., Koschak, A., & Dolphin, A. C. (2015). The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacological Reviews, 67(4), 821–870.Find this resource:

Zhu, H. L., Wassall, R. D., Cunnane, T. C., & Teramoto, N. (2009). Actions of kurtoxin on tetrodotoxin-sensitive voltage-gated Na+ currents, NaV1.6, in murine vas deferens myocytes. NaunynSchmiedeberg’s Archives of Pharmacology, 379(5), 453–460.Find this resource:

Zhuo, M. (2014). Long-term potentiation in the anterior cingulate cortex and chronic pain. Philosophical Transactions of the Royal Society B: Biological Sciences, 369(1633), 20130146.Find this resource:

Ziegler, D., Duan, W. R., An, G., Thomas, J. W., & Nothaft, W. (2015). A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain. Pain, 156(10), 2013–2020.Find this resource: