Journal
PAIN
Volume 101, Issue 1-2, Pages 109-116Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S0304-3959(02)00303-2
Keywords
antinociception; cone snail venom-derived peptides; conantokins; central sensitization; neuropathic pain
Categories
Funding
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA008377] Funding Source: NIH RePORTER
- NIDA NIH HHS [DA08377] Funding Source: Medline
- NINDS NIH HHS [NS211445] Funding Source: Medline
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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 (ED50 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: ED50 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% Cl, 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. (C) 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
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