Spinal actions of ω‐conotoxins, CVID, MVIIA and related peptides in a rat neuropathic pain model

Abstract

BACKGROUND AND PURPOSEAntagonists of the N-type voltage gated calcium channel (VGCC), Cav2.2, have a potentially important role in the treatment of chronic neuropathic pain. ω-conotoxins, such MVIIA and CVID are effective in neuropathic pain models. CVID is reported to have a greater therapeutic index than MVIIA in neuropathic pain models, and it has been suggested that this is due to faster reversibility of binding, but it is not known whether this can be improved further. EXPERIMENTAL APPROACHWe examined the potency of CVID, MVIIA and two intermediate hybrids ([K10R]CVID and [R10K]MVIIA) to reverse signs of neuropathic pain in a rat nerve ligation model in parallel with production of side effects. We also examined the potency and reversibility to inhibit primary afferent synaptic neurotransmission in rat spinal cord slices. KEY RESULTSAll ω-conotoxins produced dose-dependent reduction in mechanical allodynia. They also produced side effects on the rotarod test and in a visual side-effect score. CVID displayed a marginally better therapeutic index than MVIIA. The hybrids had a lesser effect in the rotarod test than either of their parent peptides. Finally, the conotoxins all presynaptically inhibited excitatory synaptic neurotransmission into the dorsal horn and displayed recovery that was largely dependent upon the magnitude of inhibition and not the conotoxin type. CONCLUSIONS AND IMPLICATIONSThese findings indicate that CVID provides only a marginal improvement over MVIIA in a preclinical model of neuropathic pain, which appears to be unrelated to reversibility from binding. Hybrids of these conotoxins might provide viable alternative treatments.

Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model

“…By contrast, the therapeutic window for WIN55212 ranged between 0.8 and 2.2 and was similar to that previously reported for cannabinoid receptor agonists in the rat partial sciatic nerve ligation and spinal nerve ligation models, using a variety of pain and side‐effect assays (Fox et al, ; Scott et al, ). To put this into context, it might be noted that conotoxin MVIIA, which is approved for use in chronic pain, has a therapeutic window of 0.7–2.1 in rodent neuropathic pain models when delivered intrathecally (Scott et al, ; Jayamanne et al, ). The greater therapeutic window of JZL195 compared with WIN55212, in conjunction with its higher anti‐allodynic efficacy compared with URB597 and JZL184, suggests that JZL195 may represent an improved cannabinoid strategy for treating neuropathic pain states compared with both cannabinoid receptor agonists and selective FAAH/MAGL inhibitors.…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…A blockade of Cav2.2 using ω-conotoxin MVIIA has been shown to alleviate both inflamed and neuropathic pain [256,257]. However, regarding other VGCCs such as Cav3.1, Cav3.2, and Cav3.3, which are targets for CBD [95], it is still not known whether they are channels that are important targets in the treatment of pain.…”

Pharmacological characterization of conotoxin lt14a as a potent non-addictive analgesic

“…The traditional antinociceptive opioid drugs, such as morphine and pethidine, show a powerful antinociceptive efficacy; however, the development of tolerance and physical dependence is also a universal characteristic of these drugs (Chindo et al, 2009). As promising antinociceptive drugs, MVIIA, CVID, Vc1.2, m-and mO-conotoxins show efficient antinociceptive properties by targeting different molecular receptors (Indurthi et al, 2014b;Jayamanne et al, 2013;Klotz, 2006;Knapp et al, 2012;Wallace et al, 2008).…”