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AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies.
Neuropharmacology. 2012 Oct; 63(5):905-15.N

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+Show Affiliations

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.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22771770

Citation

Seely, Kathryn A., et al. "AM-251 and Rimonabant Act as Direct Antagonists at Mu-opioid Receptors: Implications for Opioid/cannabinoid Interaction Studies." Neuropharmacology, vol. 63, no. 5, 2012, pp. 905-15.
Seely KA, Brents LK, Franks LN, et al. AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies. Neuropharmacology. 2012;63(5):905-15.
Seely, K. A., Brents, L. K., Franks, L. N., Rajasekaran, M., Zimmerman, S. M., Fantegrossi, W. E., & Prather, P. L. (2012). AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies. Neuropharmacology, 63(5), 905-15. https://doi.org/10.1016/j.neuropharm.2012.06.046
Seely KA, et al. AM-251 and Rimonabant Act as Direct Antagonists at Mu-opioid Receptors: Implications for Opioid/cannabinoid Interaction Studies. Neuropharmacology. 2012;63(5):905-15. PubMed PMID: 22771770.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies. AU - Seely,Kathryn A, AU - Brents,Lisa K, AU - Franks,Lirit N, AU - Rajasekaran,Maheswari, AU - Zimmerman,Sarah M, AU - Fantegrossi,William E, AU - Prather,Paul L, Y1 - 2012/07/04/ PY - 2011/12/21/received PY - 2012/06/04/revised PY - 2012/06/22/accepted PY - 2012/7/10/entrez PY - 2012/7/10/pubmed PY - 2013/1/15/medline SP - 905 EP - 15 JF - Neuropharmacology JO - Neuropharmacology VL - 63 IS - 5 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/22771770/AM_251_and_rimonabant_act_as_direct_antagonists_at_mu_opioid_receptors:_implications_for_opioid/cannabinoid_interaction_studies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(12)00304-8 DB - PRIME DP - Unbound Medicine ER -