Pharmacogenetic variability in neuronal nicotinic receptor-mediated antinociception

The ability to predict interindividual differences in drug efficacy or toxi city, based on genetic factors that influence drug disposition or drug acti on, 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 in bred mouse strains (A, AKR, BALB/c, C3H/He, C57BL/6, C57BL/10, DBA/2, and S M) were surveyed for their sensitivity to the antinociceptive effects of ep ibatidine, All strains exhibited statistically significant antinociception that peaked between 10 and 20 min following the systemic injection of 50 mu g/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. I n 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 du ration of effect, epibatidine displayed approximately 20-fold higher antino ciceptive potency in the A strain compared with the C3H/He strain. The effe cts of epibatidine in both the A and C3H/He strains were dose-dependent and sensitive to antagonism by the selective neuronal nicotinic channel blocke r mecamylamine, Taken together, these data demonstrate the existence of pha rmacogenetic variability in neuronal nicotinic receptor-mediated antinocice ption between inbred stains of mice and presage the potential for similar v ariability in analgesic response to nicotinic-based analgesics among humans . Future studies will seek to identify the chromosomal loci underlying this variability. Pharmacogenetics 9:619-625 (C) 1999 Lippincott Williams & Wil kins.