Action site of adrenergic blockers to suppress the development of tolerance to morphine analgesia

The effect of locally applied adrenergic blockers in the restricted area of the central nervous system on morphine analgesia and the development of tolerance to the analgesic effect was examined in the mouse. Intrathecal (i.t.) injection of phentolamine decreased the analgesic effect of morphine administered either subcutaneous (s.c.), intracerebroventricular (i.c.v.) or i.t., while i.t. propranolol was less potent in suppressing morphine analgesia and, in particular, did not affect the analgesic effect of i.t. morphine. I.c.v. phentolamine enhanced i.t. injected morphine analgesia; on the other hand, i.c.v. propranolol tended to reduce the analgesic effect of s.c. morphine. Compared with the effect on the analgesia, i.t. administration of both phentolamine and propranolol did not affect the development of tolerance to morphine and i.p. or i.c.v. blockers suppressed the development of tolerance to s.c. or i.t. morphine analgesia. Moreover, morphine tolerance induced by i.c.v. administration was blocked by i.c.v. phentolamine. These results not only provide further evidence for the importance of the spinal and supraspinal adrenergic systems in the analgesic effects of morphine and the development of tolerance to the effect, respectively, and also suggest the difference in both the site and mechanisms involved in the production of morphine analgesia and the development of tolerance to morphine.