Reversibility of opioid receptor occupancy of buprenorphine in vivo.

The slow association and incomplete dissociation of buprenorphine from opioid receptors observed in vitro have been suggested to reduce the accessibility of opioid receptors in vivo. If so, it might be expected that buprenorphine continues to occupy opioid receptors long after the antinociceptive activity has dissipated. To examine this hypothesis, buprenorphine (46.4 microg/kg i.v.) was administered to rats 1, 2, 4 or 8 h before isolation of their forebrain membranes and the maximal binding capacity (Bmax) for [3H]-[D-Ala2, N-methyl-Phe4-Gly5-ol]-enkephalin ([3H]DAMGO) was determined to measure the number of mu-opioid receptor binding sites remaining. Extent and duration of the reduction of Bmax by buprenorphine (ED50 11.2 microg/kg 1 h post-application) correlated with the antinociceptive activity in the rat tail flick (ED50 16.4 microg/kg i.v. 1 h post-application). At 8 h after administration there was still residual antinociception but no further attenuation of Bmax was detectable. Thus receptor occupancy by buprenorphine does not cause impairment of mu-opioid receptor accessibility beyond the duration of its antinociceptive activity. Therefore, no impairment of antinociception in the case of an opioid switch is to be expected.