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.