LOSS OF TOLERANCE TO MORPHINE AFTER A CHANGE IN ROUTE OF ADMINISTRATION - CONTROL OF WITHIN-SESSION TOLERANCE BY INTEROCEPTIVE CONDITIONED-STIMULI

Tolerance to morphine analgesia (tail-immersion test) was examined aft er manipulation of two aspects of a tolerance test: 1) the route of dr ug administration and 2) the time interval between the test dosing and the tolerance test. The intravenous (IV) and intraperitoneal (IP) rou tes were used, together with a novel test for tolerance in which the t est morphine was infused IV just 2 min before measuring the opiate eff ect. The first experiment validated this test as an assay for toleranc e by examining the log dose-response (LDR) curve changes produced by d aily IP injection with 0, 20 or 200 mg/kg morphine; the IV test confir med the expected parallel shift to the right and flattening of the LDR curve. In the second experiment, all rats of two groups were injected once daily for 3 weeks with 20 mg/kg morphine and with saline except that one group received the morphine IV (and saline IP), the other mor phine IP (saline IV). The results indicated route-specific tolerance. On a test using 20 mg/kg given IV morphine, tolerance was significantl y greater in rats treated with IV morphine than in those treated IP. H owever, a larger effect on tolerance was produced by a pretest applica tion of 5 mg/kg morphine 30 min before the actual tolerance test. This manipulation was designed to ''prime'' short-term, adaptive processes hypothesized to occur within a normal tolerance test session as morph ine is taking effect. The tolerance on the test increased (equivalent to 2 to 3 fold shift in the LDR curve) when the pretest morphine was g iven with the same route as the chronic morphine, regardless of treatm ent group. It was concluded that opiate tolerance may be modulated by conditioned stimuli produced by morphine acting through different rout es. These interoceptive cues appear to modulate rapidly acquired and s hort-lived adaptive processes taking place within a given test session .