Lewis and Fischer 344 (F344) rats differ in their physiological and pharmacological responses to a variety of environmental stimuli, which have been partially attributed to endogenous opioid function. Since opioid and a2-adrenoceptor mechanisms are closely related, we have comparatively examined the contribution of both systems to antinociception in female Lewis and F344 rats by the tail-flick method. Basal responses of F344 and Lewis rats were found to be similar, both showing a slight but significant increase in reaction time along the experimental period which was not completely reversed by naloxone. Morphine exhibited a bell-shaped dose–response curve in Lewis rats, these animals being more sensitive than F344 at 1 and 5 mg/kg but less sensitive at 10 mg/kg. Clonidine up to 0.1 mg/kg was more active in F344 rats. The a2-adrenoceptor antagonist yohimbine provoked a higher hyperalgesic effect in Lewis rats and decreased morphine antinociception in both strains. The existence of a balanced contribution of opioid and a2-adrenoceptor mechanisms to control pain transmission in both strains is discussed.