Voltage-Gated Calcium Channels for the Treatment of Pain

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This entry is adapted from the peer-reviewed paper 10.3390/ijms24119223

The voltage-gated calcium channels (VGCCs) are classified in low- (T-type or Cav3) or high-voltage activation (L or Cav1, N, P/Q, and R-type or Cav2). They can be further subclassified by structural similarities (channel-forming α1-subunit) where L-(Cav1.1, Cav1.2, Cav1.3, and Cav1.4), P/Q-(Cav2.1), N-(Cav2.2), and R-(Cav2.3) channels form heteromultimers (along with auxiliary β-, α2δ, and γ-subunits) and T-type (Cav3.1, Cav3.2, and Cav3.3) channels, which are α1-subunit monomers. Pain perception is a sensory and emotionally unpleasant experience; moreover, it represents a huge personal, medical, and economic burden that pharmacotherapy targeting brain pathways is now being researched for and developed in the medical field. Obviously, acute pain does not carry the load of chronic pain that is conceived as a disease on its own and as secondary to an underlying disease (like a symptom). Chronic pain is related to neuronal adaptations and is high risk for psychological distress and sleep deprivation, among other consequences impairing the quality of life.

analgesic antinociception calcium signaling drug development pain transmission VGCCs

1. L-Type Channels

Additionally, known as the dihydropyridine channels, these L-type (long-lasting) channels exist in four different isoforms, namely Cav1.1–Cav1.4, given that Cav1.2 and Cav1.3 are more expressed in the nervous system in mammals ^[1]. More specifically, in the dorsal horn of the spinal cord, Cav1.3 are found in dendrites, while Cav1.2 are restricted to the soma, but both are believed to control neuronal hyperexcitability by regulating neuronal firing postsinaptically ^[2]. Originally, the Cav1.x research focused on the cardiovascular system, and posteriorly the interest shifted to other disease states ^[3].

The dysregulation of Cav1.2 and Cav1.3 in dorsal horn neurons would be responsible, respectively, for short-term (the increase in nociceptive pathway responsiveness) and long-term (plasticity) sensitization linked with neuropathic pain ^[4]. In neuropathic pain models, Cav1.2 and Cav1.3 isoforms would be downregulated in DRG, whereas Cav1.3 is found to be upregulated in the spinal cord ^[5]. Besides, knocking down the Ca1.2 decreased behavioral hypersensitivity and reversed the neuronal hyperexcitability in the dorsal horn ^[6]. In a recent review, Roca-Lapirot et al. ^[7] summarized that acute sensitization, hyperexcitability induced by inflammation, and allodynia or hyperalgesia induced by neuropathy can effectively be reversed when different families of calcium channels blockers such as nimodipine (dihydropyridines), verapamil (phenylalkylamines), or diltiazem (benzothiazepines) were intrathecally delivered. Li and colleagues also associated the increased expression and activity of Cav1 channels in DRG, especially Cav1.2, with sleep-deprivation-mediated persistent postoperative pain ^[8]. In this pain model, the authors revealed that intraperitoneal injection of nimodipine showed antinociceptive effects, thus corroborating the findings of Wong and colleagues by using the tail-flick test ^[9] or by Kawashiri et al. ^[10] when testing orally treated oxaliplatin-induced neuropathic rats receiving nimodipine. Alternatively, other authors showed that spinally delivered verapamil, diltiazem, and nimodipine did not show analgesic effects in the neuropathic pain models ^[11]^[12]^[13].

The pathomechanisms of migraine are related to the activation of the trigeminovascular system (TGVS), among other circuits, where cortical spreading depression (CSD) outcomes in aura preceded migraine episodes ^[14]. In this sense, if the Cav1 channels are shown to be upregulated in mouse brains subjected to episodes of CSD, then they might be involved in the pathophysiology of the condition ^[15]. The in vitro data indicated that the blockade of L-type voltage-gated calcium channels (VGCCs) by nimodipine decreased the potassium-induced CGRP release in rat dura mater ^[16]. Nimodipine also caused a partial relaxation of the rat basilar artery, as well as propranolol, via blocking L-type channels ^[17], which might reflect the effects of L-type VGCC blockers in migraine. Clinically, studies using flunarizine (a selective calcium channel antagonist) and nimodipine showed a reduction in the frequency of the headache attacks ^[18]^[19].

Overall, there is even strong evidence that L-type VGCCs are involved in pain transmission, although no analgesic effects are verified in human yields ^[7] and no consistent data from animals were attributed. It is suggested that the contrasting findings in the animal models could be attributed to the selectivity to the L-type channel subtype ^[20] or the mode of application of the antagonists/blockers ^[7]. It is important to remind that dihydropyridines demonstrate their electrophysiological specificity by mainly reducing vascular resistance, phenylalkylamines are less voltage dependent, and benzothiazepines could have their sensitivity modified by alternative splicing in Cav1.2 channels in blood vessels ^[21]^[22]. Therefore, the limitation to efficient treatments for pain would be based on the prominent expression of these channels in the cardiovascular system ^[23], which needs to be circumvented by being directly delivered to the central nervous system ^[7]. Along with that, a drug mainly targeting spinal Cav1.2 or Cav1.3 is difficult and challenging for drug development because of their different biophysical properties and significant sequence homology ^[21].

2. P/Q-Type Channels

P/Q-type (from Purkinje/Cerebellar) or Cav2.1 mediate P/Q-type Ca²⁺ currents and are included in the Cav2 family of the VGCCs ^[24]. These channels show an important role in controlling neurotransmitter release, once they are pre-synaptically located at the axon terminals and somatodendritic compartments of neurons ^[25]^[26], mainly in descending facilitatory systems from the rostral ventromedial medulla, which contributes to tactile allodynia in peripheral neuropathy ^[27]. Additionally, in streptozotocin-induced diabetic neuropathy, there was an increase in the expression of P/Q-type VGCCs in small- and medium-size neurons from DRG (ascending pain pathway) ^[28].

Luvisetto and colleagues ^[29], using Cav2.1α1 null mutant mice, found that these animals exhibit pronociceptive responses in inflammatory and neuropathic models but have an antinociceptive response against noxious thermal stimuli. Another example is the result of Fukumoto et al. ^[30] that highlighted that P/Q-type VGCCs would be pronociceptive once mice with a spontaneous mutation in those channels (producing lower voltage sensitivity of activation) show hypoalgesic responses demonstrated by a lower sensitivity to thermal (tail flick) but also mechanical (von Frey) and chemical (intraplantar formalin) stimuli.

The P/Q-type VGCCs are highly homologous to the N-type VGCCs given that the last one is the preferred target for pain therapeutic once there is no success in optimizing the specific P/Q-type VGCC blockers. Thus, small molecules are mixed N-P/Q-type VGCC blockers in pharmaceutical development ^[31]. Most of the discovered animal venom toxins are not specific to P/Q-type VGCCs, except by ω-agatoxin IVA and ω-agatoxin IVB derived from Agelenopsis aperta spider venom ^[31]^[32]. The blockade of the P/Q-type VGCCs by spinally delivered agatoxin IVA and agatoxin TK (its related peptide) display antinociceptive effects in acute inflammatory models in rodents ^[33]^[34]^[35]^[36]^[37]. However, there are controversial studies demonstrating that the agatoxin IVA could inhibit ^[38] or not inhibit pain in neuropathic pain models ^[13]^[39]. Another toxin recently studied for its analgesic effects is Tx3-3, derived from the venom of the Phoneutria nigriventer spider. The purified fraction blocks were preferentially P/Q-type and R-type VGCCs ^[40], and, in vivo, they were demonstrated to be efficient in murine models of noxious thermal stimuli (tail flick), neuropathic (partial sciatic nerve ligation and streptozotocin-induced diabetic neuropathy), and inflammatory pain ^[41]^[42], along with the fibromyalgia model ^[43].

So far, Cav2.1 are critically suggested to be important in genetic studies of familial hemiplegic migraine ^[44]^[45]^[46]. In this instance, although the increased calcium influx through P/Q-type VGCCs contributes to the cortical excitability being triggered to spread depression (aura putative mechanism), a decreased calcium current through Cav2.1 in the periaqueductal grey via a channel blockade facilitates trigeminal nociception ^[47]^[48]^[49]. Through this perspective, Inagaki et al. ^[50] studied a Cav2.1 modulator named tert-butyl dihydroquinone (BHQ), which, in a heterologous system transfected with a familial hemiplegic migraine mutation, was demonstrated to slow deactivation and inhibit the voltage-dependent activation of P/Q-type VGCCs. All in all, the BHQ effects corroborate the understanding of Cav2.1’s role in the migraine mechanism.

3. N-Type Channels

N-type (from Neuronal, non-L) or Cav2.2 were found in the dendritic shafts and presynaptic terminals of central and peripheral neurons ^[51]^[52]. They are the main contributors to the nociceptive signal transmission in the dorsal horn of the spinal cord, once there is an up-regulation in nociceptive neurons ^[53]. The inhibition or deletion of these channels evidenced their role during pain states (see review by Hoppanova and Lacinova ^[54]). Selective and specific Cav2.2 blockers are being studied in vitro or were tested in rodent pain models, and they include several ω-conotoxins derived from marine cone snails as GVIIA from Conus geographus; MVIIA and MVIIB from Conus magus; SVIA and SO-3 from Conus striatus; CVIE from Conus catus; FVIA from Conus fulmen; RVIA from Conus radiatus; TVIA from Conus tulipa; MoVIA and MoVIB from Conus moncuri; RsXXIVA from Conus regularis; and Eu1.6 from Conus eburneus (see the recent reviews by Ramirez et al. ^[55] and Trevisan and Oliveira ^[56]). Similarly, the toxins purified from the venom of the Chinese bird spider Ornithoctonus huwena showed the N-type blocker properties in electrophysiologic studies such as HWTX-X ^[57] and HWTX-XVI, but only the last toxin was tested in vivo for eliciting analgesic responses in the formalin-elicited pain model ^[58].

The toxins with Cav2.2 blocking action might also act in other channels to produce analgesia. Examples that are being studied include: GeXIVA from Conus generalis that also act in inwardly rectifying K⁺ currents (GIRK) ^[59]^[60]; Vc1.1 from Conus victoriae; and RgIA from Conus regius to target the α9-subunit-containing nicotinic acetylcholine receptors (α9-nAChR) as well as the GABA_B receptor mechanisms ^[61]^[62]^[63] (both in Phase II clinical trials); and Cd1a from the venom of the spider Ceratogyrus darlingi that interferes with Cav2.2 inactivation and the α-subunit pore, while altering the activation gating of Nav1.7 ^[64].

HVA (high-voltage-activated) VGCC activity depends on the interaction between alpha and beta subunits ^[65]. Then, small molecules such as IPPQ (a quinazoline analog), which selectively target that interface on Cav2.2, show potential for pain therapeutics. That molecule inhibited the N-type VGCC currents in sensory neurons and their pre-synaptic localization and spinal neurotransmission in vivo, thus resulting in decreased neurotransmitter release and reduced mechanical allodynia and thermal hyperalgesia in murine models of postsurgical and neuropathic pain ^[66]^[67]. That promising molecule displayed superior effects in comparison with others with the same target, such as BTT-369 (a benzoylpyrazoline analog) ^[68], based on its different kinetics and toxicity profile ^[66].

Searching for analogues of conotoxins, fluorophenoxyanilide derivatives were screened, tested, and revealed an improved activity to block N-type VGCCs ^[69]. However, no more studies were found regarding these compounds.

4. T-Type Channels

Dihydropiperidines are considered L-type VGCC blockers, but their derivatives have been described as Cav3.x inhibitors, being able to reduce pain in mice ^[70]^[71], as well as dihydropyrimidine derivatives ^[72]. Clinically existing medicines such as bepridil (a diamine used as anti-arrhythmic) and pimozine (diphenylbutylpiperidine used as antipsychotic) were also shown to block T-type VGCCs and decrease nociception in animals with colonic and bladder pain ^[73]. Still regarding piperidine derivatives, TTA-P2 is a recently synthesized selective and potent Cav3 inhibitor that was demonstrated to reduce pain responses in mice in acute inflammatory pain and diabetic neuropathy ^[74]^[75]^[76]. In the same perspective, TTA-A2 efficiently inhibits Cav3, demonstrating higher potency for Cav3.2, and it was shown to decrease pain in an irritable bowel syndrome model ^[77], nocifensive visceromotor responses to noxious bladder distension ^[78], and bortezomib-induced peripheral neuropathy ^[79]. Z944 is a piperazine-based and T-type selective antagonist that was also proven to decrease nociception in inflammatory acute and chronic pain states ^[80] as well as in a trigeminal neuralgia model ^[81] when injected systemically. Clinically, Z944 proved to be safe in healthy males and reduced the pain sensation score from both capsaicin and UV-irritated skin models ^[82]

5. R-Type Channels

Distributed in the peripheral and CNS, mainly over the cell soma and proximal neuronal dendrites ^[53], Cav2.3 or R-type (from residual) VGCCs are encoded by the CACNA1E gene (VGCC subunit alpha1 E, see the recent review by Scheinder et al. ^[83]). They are engaged in visceral nociception control; once Saegusa et al. ^[84] revealed that mice lacking the α1E subunit had altered pain responses, and Yang and Stephens ^[85] showed that partial-sciatic-nerve-ligation-induced neuropathy in the DRGs of these mice triggered drug resistance through alternative adaptive mechanisms. Alternatively, the endogenous amino acid l-cysteine modulated R-type VGCCs and increased the nociceptive behavior in an acetic acid visceral pain model in wild type mice when administered subcutaneously, intraperitoneally, or intrathecally, but had no effect in Cav2.3 knockout mice ^[86], proving Cav2.3’s role in visceral pain.

As a selective Cav2.3 inhibitor, SNX-482 from the venom of the Hysterocrates gigas spider was demonstrated to decrease R-type currents when administered intrathecally and to diminish the nociception in a model of neuropathic pain ^[87]. Another current marine toxin investigated is contulakin g (CGX) from Conus geographus, which has a mechanism of action that is dependent on the R-type VGCCs in sensory neurons and is unveiled by intrathecal injection in rodent models of inflammatory and neuropathic pain ^[88].

6. α2δ Subunit Blockade

An increased expression of the Cavα2δ auxiliary subunit of VGCCs was observed in rodents with neuropathic pain ^[89]^[90], which could contribute to enhanced pre-synaptic excitatory neurotransmitter release and related behavioral pain ^[91]^[92]. In this scenario, spinally, Cavα2δ differentially modulates N-, L-, and P/Q-types to promote behavioral hypersensitivity ^[90], but the selective and high-affinity binding in Cavα2δ inhibits abnormal neuronal activity ^[93] in a sufficient manner to provide analgesic action.

Gabapentinoids such as pregabalin, gabapentin, and mirogabalin (used to prevent and control seizures) have demonstrated therapeutic efficacy to treat pain clinically and pre-clinically (see the recent review by Chen et al. ^[94]). Although their effects can be attributed to a multitude of mechanisms, they downregulate the VGCCs and N-methyl-D-aspartate (NMDA) receptor expression and decrease excitatory neurotransmitter release by inhibiting the Cavα2δ of HVA VGCCs ^[95]^[96]. Mirogabalin is the current novel gabapentinoid being explored in the pain field. The drug shows promising results to treat pain conditions with good efficacy and tolerability ^[97].

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