The potent opioid agonist, (+)-cis-3-methylfentanyl binds pseudoirreversibly to the opioid receptor complex in vitro and in vivo: evidence for a novel mechanism of action.

Abstract

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 (delta cx binding site). Intravenous administration of (+)-cis-MF (50 micrograms/kg) to rats produced a pronounced catalepsy and also produced a wash-resistant masking of delta cx and mu binding sites in membranes prepared 120 min post-injection. Administration of 1 mg/kg i.v. of the opioid antagonist, 6-desoxy-6 beta-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 delta cx 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.

• Authors: L Band, H Xu, V Bykov, N Greig, C H Kim, A Newman, A E Jacobson, K C Rice, R B Rothman
• Journal: Life sciences (Life Sci) Vol. 47 Issue 24 Pg. 2231-40 ( 1990) ISSN: 0024-3205 [Print] Netherlands
• PMID: 2176265 (Publication Type: Journal Article)

Chemical References

• Narcotic Antagonists
• Receptors, Opioid
• Receptors, Opioid, delta
• Enkephalin, Leucine-2-Alanine
• 3-methylfentanyl
• Fentanyl

Topics

• Animals
• Brain (drug effects)
• Catalepsy (chemically induced)
• Catatonia (chemically induced)
• Cell Membrane (drug effects)
• Enkephalin, Leucine-2-Alanine (metabolism)
• Fentanyl (administration & dosage, analogs & derivatives, metabolism, pharmacology)
• In Vitro Techniques
• Injections, Intravenous
• Male
• Narcotic Antagonists
• Rats
• Rats, Inbred Strains
• Receptors, Opioid (metabolism)
• Receptors, Opioid, delta