Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice

The biochemical processes underlying opiate addiction are complex, but n-methyl-d-aspartate receptor (NMDAR) dysfunction appears to be one contributing factor. NMDAR antagonists, including MK-801 and memantine, have previously been shown to assuage symptoms stemming from opiate withdrawal. The conantokins are a small family of naturally occurring peptide toxins known to specifically antagonize the NMDAR. In the present study, the effects of wild-type and variant conantokins on the suppression of naloxone-induced jumping in morphine-dependent mice were evaluated. Our results demonstrate that NR2B-selective conantokins, viz., con-G, con-G[S16Y] and con-G[γ7K], are potent inhibitors of naloxone-induced jumping at low doses (2–15 nmol/kg) compared with con-T, con-R[1-17], and small-molecule antagonists of the NMDAR, including the NR2B-selective agent, ifenprodil. We conclude that the NR2B-selective conantokins may find utility as neuropharmacological tools for probing NMDAR-related mechanisms of opiate dependence.