Homology‐guided mutational analysis reveals the functional requirements for antinociceptive specificity of collapsin response mediator protein 2‐derived peptides

Abstract

This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

CRMP2 and voltage-gated ion channels: potential roles in neuropathic pain

“…Importantly, CRMP2-derived peptides did not demonstrate toxicity or other adverse side effects associated with targeting VGCCs via direct and state-dependent channel blockers. CRMP2-targeted small molecules in development against VGSCs as well as VGCCs [92, 100–101, 103, 117, unpublished data] have also shown similar profiles of preclinical success. Together, this work precipitates the necessary advancement of CRMP2-centered drug discovery ventures into studies for diverse clinical pain indications and other channelopathies.…”

Recent advances in targeting ion channels to treat chronic pain

“…Of relevance here is that a range of animal models of pain are used to determine the effects of potential analgesics on parameters such as hypersensitivity and allodynia and on parameters related to central sensitization such as wind‐up (an activity‐dependent persistent increase in neuronal firing). These models of chronic pain include not only the widely used spinal nerve ligation, partial sciatic nerve ligation and chronic constriction injury models but also more specific models such as Freund's complete adjuvant‐induced inflammatory pain (Lee et al ., ), the carrageenan model of peripheral inflammation (Nerandzic et al ., ), post‐surgical pain and HIV‐induced sensory neuropathy models (Moutal et al ., ) and the chronic visceral hypersensitivity model (Castro et al ., ).…”

“…Equally, ionotropic receptors, in particular, excitatory NMDA glutamate (Haley and Dickenson, ) and inhibitory GABA and glycine (Zeilhofer et al ., ) receptors and additional targets such as P2X ATP receptors (Bernier et al ., ), offer further possibilities. In addition to pore‐forming subunits as molecular targets, neuronal excitability may also be modulated via binding partners such as voltage‐gated Ca 2+ channel auxiliary α2δ subunits (the binding site for gabapentinoids; Gong et al ., ) and collapsin response mediator protein 2, which modulates voltage‐gated Ca 2+ (and potentially Na + ) channel activity in pain states (Moutal et al ., ). It is also clear that academic and pharmaceutical industry drug development programmes are starting to deliver lead low MW entities and biological agents to target ion channels or associated proteins.…”

Targeting the CaVα-β interaction yields a selective antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy

“…45 increased withdrawal latency to a heat stimulus in naïve rats ( Fig 5A), demonstrating anti-nociceptive potential. Furthermore, CaV2.2 is known to be involved in post-surgical pain [17], neuropathic pain [62], chemotherapy induced neuropathy [24], HIV-induced sensory neuropathy [37] and Neurofibromatosis type 1 (NF1) related pain [40]. Thus, we performed an analgesic appraisal of 45 on heat and tactile sensitivity of rats in vivo.…”