Adrenergic function and the development of analgesic tolerance to morphine

Whether or not the suppressive effect of alpha- and beta-adrenergic blockers, phentolamine and propranolol, on the development of tolerance to morphine could be substituted for each other was investigated in mice. Daily co-administration of either one of the blockers with morphine suppressed the development of analgesic tolerance to morphine as far as the treatment was continued without affecting the analgesic effect per se; however, the suppressive effect was lost from the day of the substitution for the other blocker and tolerance developed as rapidly as in the control group treated with morphine alone. Co-administration of both blockers with morphine also maintained the analgesic effect on the 1st day for 10 days, but when the administration of either one or both blockers was eliminated from the 6th day, the development of tolerance was initiated. These results suggest that the mechanisms of alpha- and beta-blockers for the suppression of the development of analgesic tolerance to morphine are different from each other and that adrenergic blockers may produce a specific alteration in the mechanism for the development of tolerance to morphine.