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date: 18 March 2019

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 PainClick to view larger

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.

Conclusion

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.

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