Development of tolerance to the analgesic activity of mu agonists after continuous infusion of morphine, meperidine or fentanyl in rats.

We investigated the role of intrinsic activity in the ability of mu-opioid agonists to produce tolerance to the analgesic effects of other mu agonists. Dose-response curves were generated for each test drug before and 24 hr after 1 week s.c. agonist infusions, using a tail-flick procedure in male rats. Morphine tolerance was dose-dependent over a range of doses, 0.3 to 1.4 mg/kg/hr, infused for 7 days by osmotic pump; 0.8 mg/kg/hr (1/4 acute ED50/hr) shifted the morphine dose-response curve roughly 2-fold to the right. Morphine, fentanyl or meperidine were then infused for 1 week to induce tolerance; doses were based on equipotent acute s.c. doses (1/4 ED50/hr). Drugs tested for analgesic activity, using a cumulative dosing procedure, included morphine, fentanyl, meperidine, methadone, buprenorphine, etorphine and levorphanol. The relative potency (RP) was calculated for each animal by dividing the preinfusion analgesic ED50 by the postinfusion ED50. The potency of morphine, fentanyl, meperidine and levorphanol decreased after a 7-day infusion of 0.8 mg/kg/hr morphine (RP = 0.44-0.70), but the potency of etorphine (RP = 0.85) and methadone (RP = 0.78) were not significantly changed. Chronic infusions of 6.25 mg/kg/hr meperidine produced more tolerance than did morphine (RP = 0.11-0.51). No significant change in analgesic potency was seen in six of the seven test drugs after infusions of 0.01 mg/kg/hr fentanyl (RP = 0.81-1.27). Buprenorphine did not produce an analgesic response in rats that received infusions of any of the three mu agonists. The RP of drugs with low intrinsic activity was lower than the RP of high efficacy drugs.(ABSTRACT TRUNCATED AT 250 WORDS)