RÉSUMÉ
BACKGROUND AND PURPOSE: Antagonists of the N-type voltage gated calcium channel (VGCC), Cav 2.2, 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 APPROACH: We 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 RESULTS: All 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 IMPLICATIONS: These 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.
Sujet(s)
Analgésiques non narcotiques/pharmacologie , Névralgie/traitement médicamenteux , Conotoxines-oméga/pharmacologie , Analgésiques non narcotiques/administration et posologie , Analgésiques non narcotiques/toxicité , Animaux , Inhibiteurs des canaux calciques/administration et posologie , Inhibiteurs des canaux calciques/pharmacologie , Inhibiteurs des canaux calciques/toxicité , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Hyperalgésie/traitement médicamenteux , Mâle , Névralgie/physiopathologie , Peptides/administration et posologie , Peptides/composition chimique , Peptides/pharmacologie , Rats , Rat Sprague-Dawley , Test du rotarod , Moelle spinale/effets des médicaments et des substances chimiques , Moelle spinale/métabolisme , Transmission synaptique/effets des médicaments et des substances chimiques , Conotoxines-oméga/administration et posologie , Conotoxines-oméga/toxicitéRÉSUMÉ
Highly selective Ca(v)2.2 voltage-gated calcium channel (VGCC) inhibitors have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Cone snail venoms provided the first drug in class with FDA approval granted in 2005 to Prialt (omega-conotoxin MVIIA, Elan) for the treatment of neuropathic pain. Since this pioneering work, major efforts underway to develop alternative small molecule inhibitors of Ca(v)2.2 calcium channel have met with varied success. This review focuses on the properties of the Ca(v)2.2 calcium channel in different pain states, the action of omega-conotoxins GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved Ca(v)2.2 calcium channel therapeutics, and finally the development of small molecules for the treatment of chronic pain.
