Important Role of Adrenergic Function in the Development of Analgesic Tolerance to Morphine in Mice

The involvement of a catecholaminergic mechanism in the production of morphine analgesia and the development of tolerance to the effect has been suggested. Here, using various adrenergic blockers, the role of adrenergic function in the mechanism was examined. Phentolamine (alpha 1 + alpha 2-blocker, 10, 1 and 0.5 mg/kg), prazosin (alpha 1-blocker, 0.1 and 0.02 mg/kg), propranolol (beta 1 + beta 2-blocker, 10, 1 and 0.5 mg/kg), metoprolol (beta 1-blocker, 10 and 1 mg/kg) did not affect morphine analgesia, but dose-dependently suppressed the development of tolerance to morphine. Yohimbine (alpha 2-blocker, 5 and 1 mg/kg) dose-dependently antagonized morphine analgesia in naive animals and delayed the development of tolerance to morphine. Pindolol (beta 1 + beta 2-blocker but is devoid of membrane stabilizing activity) suppressed the development of tolerance to morphine analgesia; however, d-propranolol, which possesses membrane stabilizing activity but lacks beta-blocking activity, could not prevent the development of tolerance. Thus, the suppressive effect of propranolol on the development of tolerance is not due to membrane stabilizing properties. Not only the non-selective adrenergic blockers, phentolamine and propranolol, but also the selective blockers of each receptor subtype, prazosin and metoprolol, suppressed the development of tolerance. This fact may suggest the importance of the equilibrated state of adrenergic functions in the mechanism for the development of tolerance to morphine.