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Inhibition of forebrain μ-opioid receptor signaling by low concentrations of rimonabant does not require cannabinoid receptors and directly involves μ-opioid receptors.
Neurochem Int. 2012 Aug; 61(3):378-88.NI

Abstract

Increasing number of publications shows that cannabinoid receptor 1 (CB(1)) specific compounds might act in a CB(1) independent manner, including rimonabant, a potent CB(1) receptor antagonist. Opioids, cannabinoids and their receptors are well known for their overlapping pharmacological properties. We have previously reported a prominent decrease in μ-opioid receptor (MOR) activity when animals were acutely treated with the putative endocannabinoid noladin ether (NE). In this study, we clarified whether the decreased MOR activation caused by NE could be reversed by rimonabant in CB(1) receptor deficient mice. In functional [(35)S]GTPγS binding assays, we have elucidated that 0.1mg/kg of intraperitoneal (i.p.) rimonabant treatment prior to that of NE treatment caused further attenuation on the maximal stimulation of Tyr-d-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO), which is a highly specific MOR agonist. Similar inhibitory effects were observed when rimonabant was injected i.p. alone and when it was directly applied to forebrain membranes. These findings are cannabinoid receptor independent as rimonabant caused inhibition in both CB(1) single knockout and CB(1)/CB(2) double knockout mice. In radioligand competition binding assays we highlighted that rimonabant fails to displace effectively [(3)H]DAMGO from MOR in low concentrations and is highly unspecific on the receptor at high concentrations in CB(1) knockout forebrain and in their wild-type controls. Surprisingly, docking computational studies showed a favorable binding position of rimonabant to the inactive conformational state of MOR, indicating that rimonabant might behave as an antagonist at MOR. These findings were confirmed by radioligand competition binding assays in Chinese hamster ovary cells stably transfected with MOR, where a higher affinity binding site was measured in the displacement of the tritiated opioid receptor antagonist naloxone. However, based on our in vivo data we suggest that other, yet unidentified mechanisms are additionally involved in the observed effects.

Authors+Show Affiliations

Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt. 62, H-6726 Szeged, Hungary.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22613132

Citation

Zádor, Ferenc, et al. "Inhibition of Forebrain Μ-opioid Receptor Signaling By Low Concentrations of Rimonabant Does Not Require Cannabinoid Receptors and Directly Involves Μ-opioid Receptors." Neurochemistry International, vol. 61, no. 3, 2012, pp. 378-88.
Zádor F, Otvös F, Benyhe S, et al. Inhibition of forebrain μ-opioid receptor signaling by low concentrations of rimonabant does not require cannabinoid receptors and directly involves μ-opioid receptors. Neurochem Int. 2012;61(3):378-88.
Zádor, F., Otvös, F., Benyhe, S., Zimmer, A., & Páldy, E. (2012). Inhibition of forebrain μ-opioid receptor signaling by low concentrations of rimonabant does not require cannabinoid receptors and directly involves μ-opioid receptors. Neurochemistry International, 61(3), 378-88. https://doi.org/10.1016/j.neuint.2012.05.015
Zádor F, et al. Inhibition of Forebrain Μ-opioid Receptor Signaling By Low Concentrations of Rimonabant Does Not Require Cannabinoid Receptors and Directly Involves Μ-opioid Receptors. Neurochem Int. 2012;61(3):378-88. PubMed PMID: 22613132.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of forebrain μ-opioid receptor signaling by low concentrations of rimonabant does not require cannabinoid receptors and directly involves μ-opioid receptors. AU - Zádor,Ferenc, AU - Otvös,Ferenc, AU - Benyhe,Sándor, AU - Zimmer,Andreas, AU - Páldy,Eszter, Y1 - 2012/05/18/ PY - 2011/12/21/received PY - 2012/04/12/revised PY - 2012/05/10/accepted PY - 2012/5/23/entrez PY - 2012/5/23/pubmed PY - 2013/1/23/medline SP - 378 EP - 88 JF - Neurochemistry international JO - Neurochem Int VL - 61 IS - 3 N2 - Increasing number of publications shows that cannabinoid receptor 1 (CB(1)) specific compounds might act in a CB(1) independent manner, including rimonabant, a potent CB(1) receptor antagonist. Opioids, cannabinoids and their receptors are well known for their overlapping pharmacological properties. We have previously reported a prominent decrease in μ-opioid receptor (MOR) activity when animals were acutely treated with the putative endocannabinoid noladin ether (NE). In this study, we clarified whether the decreased MOR activation caused by NE could be reversed by rimonabant in CB(1) receptor deficient mice. In functional [(35)S]GTPγS binding assays, we have elucidated that 0.1mg/kg of intraperitoneal (i.p.) rimonabant treatment prior to that of NE treatment caused further attenuation on the maximal stimulation of Tyr-d-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO), which is a highly specific MOR agonist. Similar inhibitory effects were observed when rimonabant was injected i.p. alone and when it was directly applied to forebrain membranes. These findings are cannabinoid receptor independent as rimonabant caused inhibition in both CB(1) single knockout and CB(1)/CB(2) double knockout mice. In radioligand competition binding assays we highlighted that rimonabant fails to displace effectively [(3)H]DAMGO from MOR in low concentrations and is highly unspecific on the receptor at high concentrations in CB(1) knockout forebrain and in their wild-type controls. Surprisingly, docking computational studies showed a favorable binding position of rimonabant to the inactive conformational state of MOR, indicating that rimonabant might behave as an antagonist at MOR. These findings were confirmed by radioligand competition binding assays in Chinese hamster ovary cells stably transfected with MOR, where a higher affinity binding site was measured in the displacement of the tritiated opioid receptor antagonist naloxone. However, based on our in vivo data we suggest that other, yet unidentified mechanisms are additionally involved in the observed effects. SN - 1872-9754 UR - https://www.unboundmedicine.com/medline/citation/22613132/Inhibition_of_forebrain_μ_opioid_receptor_signaling_by_low_concentrations_of_rimonabant_does_not_require_cannabinoid_receptors_and_directly_involves_μ_opioid_receptors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(12)00175-1 DB - PRIME DP - Unbound Medicine ER -