title: Spinal actions of ω-conotoxins, CVID, MVIIA and related peptides in a rat neuropathic pain model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Pain Management Research Institute, Kolling Institute, Northern Clinical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Jayamanne
authors.forename: H J
authors.initials: HJ
authors.lastname: Jeong
authors.forename: C I
authors.initials: CI
authors.lastname: Schroeder
authors.forename: R J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: M J
authors.initials: MJ
authors.lastname: Christie
authors.forename: C W
authors.initials: CW
authors.lastname: Vaughan
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D020960:omega-Conotoxins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C461486:AM336; D018712:Analgesics, Non-Narcotic; D002121:Calcium Channel Blockers; D010455:Peptides; D020960:omega-Conotoxins; C078452:ziconotide
keywords: calcium channel; conotoxin; neuropathic; pain; synaptic neurotransmission