Tolerance to the analgesic effects of opioids have been reported to include unconditioned (physiological) and conditioned (associative) components. The purpose of the current study was to investigate the genetic and environmental factors important in the development of tolerance by using three inbred strains of mice with varying opiate receptor concentration and acute behavioral response to opioids: C57BL/6J, CXBK/ByJ, and CXBH/ByJ mice. Each strain was divided into three groups; each group received two injections per day as part of the tolerance development procedure. One group of each strain was administered an opioid (etonitazene) specifically paired with the testing room and a second injection of saline in the home colony (paired). The second group of each strain was administered saline in the testing room and etonitazene in the home colony (unpaired). A third group of each strain was administered saline in both the testing room and home colony (control). Etonitazene and saline were administered in this manner for 4 days. On day 5, animals were tested for hot-plate analgesic response following administration of etonitazene. There was a significant effect of treatment condition (paired, unpaired, control) on etonitazene-induced analgesia. In all strains, only the paired treatment condition demonstrated tolerance to the analgesic effects of etonitazene compared to the control groups. There was no significant effect of genotype or a genotype x condition interaction. Thus, genotype significantly affects the acute analgesic effects of opioids but did not affect the development of conditioned tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)