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Long-term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox.
- Source :
-
Pharmacology research & perspectives [Pharmacol Res Perspect] 2021 Dec; Vol. 9 (6), pp. e00887. - Publication Year :
- 2021
-
Abstract
- Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan <superscript>®</superscript> ). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations. Due to the short half-life of naloxone, renarcotization can occur if the ingested opioid agonist remains in the body longer. Moreover, because antagonism by naloxone is surmountable, renarcotization can also occur in the presence of naloxone if a relatively larger dose of opioid agonist is taken. In such circumstances, a long-lasting, non-surmountable antagonist would offer an improvement in overdose treatment. Methocinnamox (MCAM) has been reported to have a long duration of antagonist action at mu opioid receptors in vivo. In HEK cells expressing the human mu opioid receptor, MCAM antagonism of mu agonist-inhibition of cAMP production was time-dependent, non-surmountable and non-reversible, consistent with (pseudo)-irreversible binding. In vivo, MCAM injected locally into the rat hindpaw antagonized mu agonist-mediated inhibition of thermal allodynia for up to 96 h. By contrast, antagonism by MCAM of delta or kappa agonists in HEK cells and in vivo was consistent with simple competitive antagonism. Surprisingly, MCAM also shifted the concentration-response curves of mu agonists in HEK cells in the absence of receptor reserve in a ligand-dependent manner. The shift in the [D-Ala <superscript>2</superscript> ,N-MePhe <superscript>4</superscript> ,Gly-ol <superscript>5</superscript> ]-enkephalin (DAMGO) concentration-response curve by MCAM was insensitive to naloxone, suggesting that in addition to (pseudo)-irreversible orthosteric antagonism, MCAM acts allosterically to alter the affinity and/or intrinsic efficacy of mu agonists.<br /> (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)
- Subjects :
- Allosteric Regulation drug effects
Animals
Cyclic AMP metabolism
Enkephalin, Ala(2)-MePhe(4)-Gly(5)- pharmacology
HEK293 Cells
Humans
Ligands
Male
Naloxone pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Opioid, mu metabolism
Time Factors
Cinnamates pharmacology
Morphine Derivatives pharmacology
Narcotic Antagonists pharmacology
Receptors, Opioid, mu antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2052-1707
- Volume :
- 9
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Pharmacology research & perspectives
- Publication Type :
- Academic Journal
- Accession number :
- 34713624
- Full Text :
- https://doi.org/10.1002/prp2.887