The offset of morphine tolerance in rats and mice

1. In rats and mice made tolerant to morphine by pretreatment with the drug, the shift to the right of the log dose/analgesic response line for in naive animals occurs without significant change in slope provided that sufficient time is allowed for elimination of pretreatment drug. 2. Responsiveness to the analgesic effects of morphine, given together with cycloheximide to prevent reinforcement of tolerance, was measured in rats (paw pressure method) and mice (hot plate method) at intervals during 1-23 days following cessation of a variety of regimens of tolerance-inducing drug treatments. 3. A biphasic pattern of recovery of responsiveness was observed, which was independent of the regimen or the drug (morphine, methadone or diamorphine) used to induce tolerance. Estimates of the rates of the first, fast phase are imprecise but the rate of the second phase of offset, from 4th day after cessation of pretreatment had, in rats, a mean half-time of 13.2 plus or minus 0.53 days-for all pretreatments combined, there being no significant differences between the various pretreatment regimens employed. In mice, similarly, a biphasic recovery of analgesic responsiveness was seen after morphine pretreatment, the mean half-time of the slower phase being 17.4 days. 4. Precipitation of an acute withdrawal syndrome in rats by naloxone HCl given 6 h after the final injection of a tolerance-inducing treatment with morphine did not affect the subsequent rate of recovery from tolerance. 5. During the period following a tolerance-inducing pretreatment with morphine in mice, the rate of attenuation of the naloxone-evoked jumping response was faster than the rate of offset of tolerance.