Pharmacological Inhibition of Voltage-gated Ca²⁺ Channels for Chronic Pain Relief

Abstract

Chronic pain is a major therapeutic problem as the current treatment options are unsatisfactory with low efficacy and deleterious side effects. Voltage-gated Ca2+ channels (VGCCs), which are multi-complex proteins consisting of α1, β, γ, and α2δ subunits, play an important role in pain signaling. These channels are involved in neurogenic inflammation, excitability, and neurotransmitter release in nociceptors. It has been previously shown that N-type VGCCs (Cav2.2) are a major pain target. U.S. FDA approval of three Cav2.2 antagonists, gabapentin, pregabalin, and ziconotide, for chronic pain underlies the importance of this channel subtype. Also, there has been increasing evidence that L-type (Cav1.2) or T-type (Cav3.2) VGCCs may be involved in pain signaling and chronic pain. In order to develop novel pain therapeutics and to understand the role of VGCC subtypes, discovering subtype selective VGCC inhibitors or methods that selectively target the inhibitor into nociceptors would be essential. This review describes the various VGCC subtype inhibitors and the potential of utilizing VGCC subtypes as targets of chronic pain. Development of VGCC subtype inhibitors and targeting them into nociceptors will contribute to a better understanding of the roles of VGCC subtypes in pain at a spinal level as well as development of a novel class of analgesics for chronic pain.

Breaking barriers to novel analgesic drug development

“…Interestingly, transmission at the first synapses in the pain pathway, glutamatergic synapses from primary sensory neurons to second-order neurons in the dorsal horn, appears to rely nearly exclusively on presynaptic Cav2.2 channels. Cav 2.2 knockout mice have reduced sensitivity to some but not all types of acute, inflammatory, and neuropathic pain (reviewed by 38 ). Cav2.2 channels can be blocked selectively by several peptides from the venom of cone snails and one of these,ω-conotoxin MVIIA (ziconitide, Prialt), is currently used to treat pain, with application by intrathecal pump.…”

Electrophysiological evidence for voltage-gated calcium channel 2 (Cav2) modulation of mechano- and thermosensitive spinal neuronal responses in a rat model of osteoarthritis

“…Voltage-gated calcium channels (VGCCs) on nociceptors play an important role in nociceptive signaling; they are critical for neurotransmitter release, the regulation of neuronal excitability and intracellular changes ( Lee, 2013 ). Studies have implicated an increase in voltage-gated Ca 2+ currents, and their potential redistribution to central or peripheral terminals, contributing to inflammation-induced increases in afferent input ( Neubert et al, 2000; Bilici et al, 2001; Lu et al, 2010; Takasusuki and Yaksh, 2011 ).…”

“…The N-type (Ca v 2.2) is of particular interest for chronic pain treatment. These channels are located both pre- and post-synaptically on spinal central afferent terminals and second-order neurons, and are crucial for neurotransmitter release, such as calcitonin gene-related peptide (CGRP), substance P (SP), and glutamate and, hence, pain transduction within the CNS ( Lee, 2013 ). The potential of targeting this point of nociceptive convergence was demonstrated by studies showing that selective conotoxins prevented the onset of hyperalgesia or allodynia, and transgenic mice lacking the Ca v 2.2 gene displayed an altered pain behavioral phenotype ( Kim et al, 2001; Saegusa et al, 2001; Scott et al, 2002 ).…”

Molecular and cellular mechanisms that initiate pain and itch

“…Our focus is on neuronal and non-neuronal cells that are critically involved in the signaling pathways of pain and itch under normal and pathological conditions. We do not consider the complementary roles of P2X receptors, acid-sensing ion channels (ASICs), hyperpolarization- activated cyclic nucleotide-gated (HCN) channels, mechanically gated piezo channels, or voltage-gated Na + , Ca 2+ , and K + channels in the initiation of touch, pain, and itch sensations, as these have been covered recently in several excellent reviews [11, 13–18]. …”