THE POTENT OPIOID AGONIST, (+)-CIS-3-METHYLFENTANYL BINDS PSEUDOIRREVERSIBILY TO THE OPIOID RECEPTOR COMPLEX INVITRO AND INVIVO - EVIDENCE FOR A NOVEL MECHANISM OF ACTION

The present study demonstrates that pretreatment of rat brain membranes with (+)-cis-3-methylfentanyl {(+)-cis-MF}, followed by extensive washing of the membranes, produces a wash-resistant decrease in the binding of [3H]-[D-ala2, D-leu5]enkephalin to the d binding site of the opioid receptor complex (δcx binding site). Intravenous administration of (+)-cis-MF (50 μg/kg) to rats produced a pronounced catalepsy and also produced a wash-resistant masking of δcx and μ binding sites in membranes prepared 120 min post-injection. Administration of 1 mg/kg i.v. of the opioid antagonist, 6-desoxy-6β-fluoronaltrexone (cycloFOXY), 100 min after the injection of (+)-cis-MF (20 min prior to the preparation of membranes) completely reversed the catatonia and restored masked δcx binding sites to control levels. This was not observed with (+)-cycloFOXY. The implications of these and other findings for the mechanism of action of (+)-cis-MF and models of the opioid receptors are discussed. © 1990.