The ability to predict interindividual differences in drug efficacy or toxicity, based on genetic factors that influence drug disposition or drug action, is fast becoming a realistic goal. The purpose of the present study was to determine whether epibatidine, a prototypical nicotinic analgesic drug, exhibits pharmacogenetic variability in antinociceptive activity. Eight inbred mouse strains (A, AKR, BALB/c, C3H/He, C57BL/6, C57BL/10, DBA/2, and SM) were surveyed for their sensitivity to the antinociceptive effects of epibatidine. All strains exhibited statistically significant antinociception that peaked between 10 and 20 min following the systemic injection of 50 microg/kg epibatidine. However, there was fourfold variability in the magnitude of peak effect between strains, with DBA/2, BALB/c and A strains showing much greater sensitivity than all others. A return to baseline nociceptive threshold at 30 min post-injection was observed for all but the A strain. In contrast, these mice exhibited significant antinociception for at least 3 h following epibatidine administration. Thus, expressing the data as area under the time-latency curve to take into account both the magnitude and duration of effect, epibatidine displayed approximately 20-fold higher antinociceptive potency in the A strain compared with the C3H/He strain. The effects of epibatidine in both the A and C3H/He strains were dose-dependent and sensitive to antagonism by the selective neuronal nicotinic channel blocker mecamylamine. Taken together, these data demonstrate the existence of pharmacogenetic variability in neuronal nicotinic receptor-mediated antinociception between inbred stains of mice and presage the potential for similar variability in analgesic response to nicotinic-based analgesics among humans. Future studies will seek to identify the chromosomal loci underlying this variability.