title: AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies.
abstract: Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). AM-251 and rimonabant are CB1R antagonist/inverse agonists employed to validate opioid-cannabinoid interactions, presumed to act selectively at CB1Rs. Therefore, the potential for direct action of these antagonists at MORs is rarely considered. This study determined if AM-251 and/or rimonabant directly bind and modulate the function of MORs. Surprisingly, AM-251 and rimonabant, but not a third CB1R inverse agonist AM-281, bind with mid-nanomolar affinity to human MORs with a rank order of affinity (K(i)) of AM-251 (251 nM) > rimonabant (652 nM) > AM281 (2135 nM). AM-251 and rimonabant, but not AM-281, also competitively antagonize morphine induced G-protein activation in CHO-hMOR cell homogenates (K(b) = 719 or 1310 nM, respectively). AM-251 and rimonabant block morphine inhibition of cAMP production, while only AM-251 elicits cAMP rebound in CHO-hMOR cells chronically exposed to morphine. AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent of these antagonists effects may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.
authors: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA. Katie.Seely@arkansas.gov
authors: Kathryn A
authors: KA
authors: Seely
authors: Lisa K
authors: LK
authors: Brents
authors: Lirit N
authors: LN
authors: Franks
authors: Maheswari
authors: M
authors: Rajasekaran
authors: Sarah M
authors: SM
authors: Zimmerman
authors: William E
authors: WE
authors: Fantegrossi
authors: Paul L
authors: PL
authors: Prather
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D063386:Cannabinoid Receptor Agonists / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006224:Cricetinae; D003412:Cricetulus; D054314:Drug Inverse Agonism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009292:Narcotic Antagonists; C485764:OPRM1 protein, human; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; C103505:AM 251; D000077285:Rimonabant; C109925:AM 281