Neuropharmacology, 2012-10, Vol.63 (5), p.905-915
2012
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- Autor(en) / Beteiligte
- Titel
- AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: Implications for opioid/cannabinoid interaction studies
- Ist Teil von
- Neuropharmacology, 2012-10, Vol.63 (5), p.905-915
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 (Ki) 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 (Kb = 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 actions of these antagonists may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice. ► CB1 antagonists AM-251 and rimonabant bind with mid-nanomolar affinity to MORs. ► AM-251 and rimonabant antagonize morphine G-protein activation and cAMP inhibition. ► AM-251, but not rimonabant, elicits cAMP rebound in morphine-treated cells. ► AM-251 and rimonabant, but not CB1 antagonist AM-281, attenuate morphine analgesia. ► AM-251 and rimonabant off-target actions at MORs confound CB1/MOR interaction studies.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-3908eISSN: 1873-7064DOI: 10.1016/j.neuropharm.2012.06.046Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3408547
- Format
- –
- Schlagworte
- Adenylyl cyclase, Analgesia, Analgesics, Non-Narcotic - adverse effects, Analgesics, Non-Narcotic - metabolism, Analgesics, Non-Narcotic - pharmacology, Analgesics, Non-Narcotic - therapeutic use, Analgesics, Opioid - adverse effects, Analgesics, Opioid - antagonists & inhibitors, Analgesics, Opioid - metabolism, Analgesics, Opioid - pharmacology, Animals, Antagonism, Antagonists, Binding, Competitive, Cannabinoid CB1 receptors, Cannabinoid Receptor Agonists - adverse effects, Cannabinoid Receptor Agonists - metabolism, Cannabinoid Receptor Agonists - pharmacology, Cannabinoid Receptor Agonists - therapeutic use, CB1 receptors, Cell activation, CHO Cells, Cricetinae, Cricetulus, Cyclic AMP, Drug Inverse Agonism, Drugs, G-protein, Guanine nucleotide-binding protein, Humans, Inverse agonists, Kinetics, Marijuana, Mice, Mice, Inbred Strains, Morphine, Morpholines - adverse effects, Morpholines - metabolism, Morpholines - pharmacology, Narcotic Antagonists - adverse effects, Narcotic Antagonists - metabolism, Narcotic Antagonists - pharmacology, Narcotic Antagonists - therapeutic use, Opioid receptors, Opioid receptors (type mu), Pain perception, Piperidines - adverse effects, Piperidines - metabolism, Piperidines - pharmacology, Piperidines - therapeutic use, Pyrazoles - adverse effects, Pyrazoles - metabolism, Pyrazoles - pharmacology, Pyrazoles - therapeutic use, Receptor, Cannabinoid, CB1 - agonists, Receptor, Cannabinoid, CB1 - antagonists & inhibitors, Receptor, Cannabinoid, CB1 - metabolism, Receptor, Cannabinoid, CB2 - agonists, Receptor, Cannabinoid, CB2 - genetics, Receptor, Cannabinoid, CB2 - metabolism, Receptors, Opioid, mu - agonists, Receptors, Opioid, mu - antagonists & inhibitors, Receptors, Opioid, mu - genetics, Receptors, Opioid, mu - metabolism, Recombinant Proteins - agonists, Recombinant Proteins - antagonists & inhibitors, Recombinant Proteins - metabolism, Side effects