Log dose/response curve flattening in rats after daily injection of opiates

Rats injected (IP) daily with 0, 20, and 200 mg/kg morphine-SO4 for 25-49 days experienced log dose/response (LDR) curve flattening (decrease in slope and/or maximum response) for analgesia (tail immersion test) produced by etorphine-HCl injected IP or intracerebroventricularly (ICV), and for latency to maximum rectal temperature increase produced by IP etorphine. Rats treated similarly with 0, 50, and 500 micrograms/kg etorphine-HCl for 32 days exhibited LDR-curve flattening for analgesia produced by etorphine and morphine (IP). In addition, a profound body weight loss produced by high-dose morphine treatment (200 mg/kg) was found not to be involved in flattening, since similar body weight decreases produced by food restriction in 0 and 20 mg/kg rats did not have this effect. Flattening, however, may be due to a rapidly acquired and rapidly lost within-session (acute) tolerance. When flattening was not seen at short intervals after IP or ICV test etorphine doses, flattening was seen when rats were retested at longer test intervals. Forty-eight hours after cessation of chronic etorphine treatment, flattening of the etorphine analgesia LDR curve was lost, but parallel shift was unaffected. Similarly, 200 mg/kg morphine-treated rats lost morphine tolerance more rapidly than 20 mg/kg-treated rats during the first 12 days after the last treatment injection. Subsequently, however, levels of the analgesia and the amounts of tolerance loss were comparable in both chronically treated groups. The data support the notion that chronic tolerance reflects an enhancement or prolongation of acute tolerance.