Buprenorphine: differential interaction with opiate receptor subtypes in vivo.

The mixed agonist-antagonist buprenorphine previously was shown to display a bell-shaped dose-response curve with peak agonistic (antinociceptive) opiate effects at approximately 0.5 mg/kg s.c., 60 min after the dose and a gradual decline of the effects in the dosage range between 0.5 to 10 mg/kg (electrically induced vocalization test). In vitro, buprenorphine as well as the potent pure agonist etorphine possessed very high affinity for all of the opiate receptor subtypes that are labeled by the universal tracer [3H]diprenorphine. However, in vivo, [3H]buprenorphine and [3H]etorphine appeared to label preferentially a subset of the opiate receptor sites; the labeled subset may be identical to or include the mu receptor sites, since these sites were also labeled with high affinity by [3H]naloxone, a mu preferring antagonist ligand. Buprenorphine saturated this opiate receptor subpopulation in its agonistic dosage range (less than or equal to 0.5 mg/kg). Moreover, buprenorphine saturated the remaining receptor subpopulation, labeled in vivo by [3H]diprenorphine, over its antagonistic dosage range (0.5--10 mg/kg). Cooperative receptor binding behavior of buprenorphine was not detectable. These results are consistent with the hypothesis that noncompetitive autoinhibition occurs among the opiate receptor subtypes.