Chronic morphine induces tolerance and desensitization of mu-opioid receptor but not down-regulation in rabbit.

Tolerance to chronic morphine treatment was studied in adult rabbits and modifications in the number and the state of coupling of the mu-opioid receptors were investigated in the cerebellum. Tolerance was induced by the subcutaneous injection of progressively increasing doses of morphine (5-100 mg/kg/injection) over 6 days and its occurrence was controlled by a nociceptive test: electrical stimulation of the dental pulp. At the end of the treatment, the rabbits were tolerant to the analgesic effects of morphine and the tolerance phenomenon correlated well with a significant decrease in the adenylate cyclase inhibition (approximately 60%). The functional uncoupling between the enzyme and the mu-opioid receptor was accompanied neither by a decrease in the number of high affinity receptors measured by equilibrium binding techniques (Kd = 0.19 +/- 0.03 in control vs. 0.11 +/- 0.04 nM in tolerant animals; Bmax = 322 +/- 62 vs. 362 +/- 58 fmol/mg of protein), nor by a modification of the physical coupling between the receptor and its G-protein. It can be concluded that desensitization, under our experimental conditions, can be clearly distinguished from down-regulation.