INFLUENCE OF CONTINUOUS LEVELS OF FENTANYL IN RATS ON THE MU-OPIOID RECEPTOR IN THE CENTRAL-NERVOUS-SYSTEM

The highly potent and efficacious mu-opioid agonist fentanyl was SC in fused into rats with submaximal analgesic doses (0-1.14 mu mol/kg/day) continuously for 8 days, checked by the constant daily urinary recove ry of intact drug (0.43 +/- 0.031% of the daily dose). Tail-flick late ncies measured at 24 (day 1) and 48 h (day 2) after starting the infus ion were increased in a dose-dependent fashion compared with those bef ore the infusion (day 0). However, at day 8, the latencies were increa sed only weakly, not significantly, revealing tolerance to the antinoc iceptive activity of fentanyl. Fentanyl at all doses showed no signifi cant effect on the capacity (B-max) and affinity (K-d) of the mu-opioi d receptor binding of DAMGO to whole brain (B-max 126.2 +/- 3.00 fmol/ mg protein, K-d 1.00 +/- 0.04 nM) and spinal cord (B-max 48.24 +/- 2.7 1 fmol/mg protein, K-d 1.93 +/- 0.13 nM) membranes gained from the rat s after killing them at day 8. Gpp(NH)p increased the K-d for brain an d spinal cord sites by 3.09 and 2.65, respectively, independent of the fentanyl dose. The infusion with fentanyl did not alter the basal and forskolin-stimulated adenylate cyclase activity in the whole brain me mbranes, nor did it change the inhibition of the forskolin-stimulated activity by DAMGO. It is concluded that, in rats, constant long-term b ody levels of highly potent mu-agonists result in a tolerant state tha t, however, does not produce overall changes in the parameters of thei r specific receptor sites in the CNS, i.e., receptor capacity and affi nity, and in the events closely related to them, i.e., their regulatio n by GTP and of adenylate cyclase. This does not exclude such possible changes to be restricted to specific regions in the CNS. (C) 1997 Els evier Science Inc.