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 a nd modifications in the number and the state of coupling of the mu-opi oid receptors were investigated in the cerebellum. Tolerance was induc ed by the subcutaneous injection of progressively increasing doses of morphine (5-100 mg/kg/injection) over 6 days and its occurrence was co ntrolled by a nociceptive test: electrical stimulation of the dental p ulp. At the end of the treatment, the rabbits were tolerant to the ana lgesic effects of morphine and the tolerance phenomenon correlated wel l with a significant decrease in the adenylate cyclase inhibition (app roximate to 60%). The functional uncoupling between the enzyme and the mu-opioid receptor was accompanied neither by a decrease in the numbe r of high affinity receptors measured by equilibrium binding technique s (K-d = 0.19 +/- 0.03 in control vs. 0.11 +/- 0.04 nM in tolerant ani mals; B-max = 322 +/- 62 vs. 362 +/- 58 fmol/mg of protein), nor by a modification of the physical coupling between the receptor and its G-p rotein. It can be concluded that desensitization, under our experiment al conditions, can be clearly distinguished from down-regulation.