Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T.
Subunit non-selective N-methyl-D-aspartate (NMDA) receptor antagonists reduce injury-induced pain behavior, but generally produce unacceptable side effects. In this study, we examined the antinociceptive and motor effects of cone snail venom-derived peptides, conantokins G and T (conG and conT), which are selective inhibitors of the NR2B or NR2A and NR2B subtypes of the NMDA receptor, respectively. We tested the effects of conG and conT in models of tissue (formalin test), nerve injury (partial sciatic nerve ligation) and inflammation-induced (intraplantar Complete Freund's Adjuvant; CFA) pain in mice. In the formalin test, intrathecal (i.t.) conG or conT suppressed the ongoing pain behavior (ED(50) and 95% confidence intervals (CI), 11 (7-19) and 19 (11-33), respectively) at doses that were 17-27 times lower than those required to impair motor function (accelerating rotarod treadmill test: ED(50) and 95% CI, 300 (120-730) and 320 (190-540) pmol, respectively). By comparison, SNX-111, an N-type voltage-sensitive calcium channel antagonist that is also derived from cone snail venom, produced significant motor impairment at a dose (3.0 pmol, i.t.) that was only partially efficacious in the formalin test. Furthermore, conG reversed the allodynia produced by nerve injury, with greater potency on thermal (ED50 and 95% CI, 24 (10-55) pmol) than on mechanical allodynia (59 (33-105) pmol). Finally, a single dose of conG (100 pmol, i.t.) also reduced CFA-evoked thermal and mechanical allodynia. Taken together, these results demonstrate that conantokins exhibit potent antinociceptive effects in several models of injury-induced pain. The study supports the notion that drugs directed against subtypes of the NMDA receptor, by virtue of their reduced side-effect profile, hold promise as novel therapeutic agents for the control of pain.
Malmberg
Annika B
AB
Department of Anatomy 0452, University of California, San Francisco, San Francisco, CA 94143-0452, USA.
Gilbert
Heather
H
McCabe
R Tyler
RT
Basbaum
Allan I
AI
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020916:Conotoxins / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008978:Mollusk Venoms / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009443:Neuritis / Q000188:drug therapy; D009619:Nociceptors / Q000187:drug effects*; D010147:Pain Measurement; D010455:Peptides / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012585:Sciatica / Q000188:drug therapy*
D020916:Conotoxins; D018691:Excitatory Amino Acid Antagonists; D036341:Intercellular Signaling Peptides and Proteins; D008978:Mollusk Venoms; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C063571:conantokin-T; C055407:conotoxin GV