The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Wilkerson, Jenny L.ca
• dc.contributor.author Ghosh, Sudeshnaca
• dc.contributor.author Mustafa, Mohammedca
• dc.contributor.author Abdullah, Rehab A.ca
• dc.contributor.author Niphakis, Micah J.ca
• dc.contributor.author Cabrera Ortega, Robertoca
• dc.contributor.author Maldonado, Rafael, 1961-ca
• dc.contributor.author Cravatt, Benjamin F.ca
• dc.contributor.author Lichtman, Aron H.ca
• dc.date.accessioned 2018-03-23T13:18:31Z
• dc.date.available 2018-03-23T13:18:31Z
• dc.date.issued 2017
• dc.description.abstract Although opioids are highly efficacious analgesics, their abuse potential and other untoward side effects diminish their therapeutic utility. The addition of non-opioid analgesics offers a promising strategy to reduce required antinociceptive opioid doses that concomitantly reduce opioid-related side effects. Inhibitors of the primary endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) show opioid-sparing effects in preclinical models of pain. As simultaneous inhibition of these enzymes elicits enhanced antinociceptive effects compared with single enzyme inhibition, the present study tested whether the dual FAAH-MAGL inhibitor SA-57 [4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester] produces morphine-sparing antinociceptive effects, without major side effects associated with either drug class. SA-57 dose-dependently reversed mechanical allodynia in the constriction injury (CCI) of the sciatic nerve model of neuropathic pain and carrageenan inflammatory pain model. As previously reported, SA-57 was considerably more potent in elevating anandamide (AEA) than 2-arachidonyl glycerol (2-AG) in brain. Its anti-allodynic effects required cannabinoid (CB)1 and CB2 receptors; however, only CB2 receptors were necessary for the anti-edematous effects in the carrageenan assay. Although high doses of SA-57 alone were required to produce antinociception, low doses of this compound, which elevated AEA and did not affect 2-AG brain levels, augmented the antinociceptive effects of morphine, but lacked cannabimimetic side effects. Because of the high abuse liability of opioids and implication of the endocannabinoid system in the reinforcing effects of opioids, the final experiment tested whether SA-57 would alter heroin seeking behavior. Strikingly, SA-57 reduced heroin-reinforced nose poke behavior and the progressive ratio break point for heroin. In conclusion, the results of the present study suggest that inhibition of endocannabinoid degradative enzymes represents a promising therapeutic approach to decrease effective doses of opioids needed for clinical pain control, and may also possess therapeutic potential to reduce opioid abuse.
• dc.format.mimetype application/pdf
• dc.identifier.citation Wilkerson JL, Ghosh S, Mustafa M, Abdullah RA, Niphakis MJ, Cabrera R et al. The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in mice. Neuropharmacology. 2017 Mar 1;114:156-67. DOI: 10.1016/j.neuropharm.2016.11.015
• dc.identifier.doi http://dx.doi.org/10.1016/j.neuropharm.2016.11.015
• dc.identifier.issn 0028-3908
• dc.identifier.uri http://hdl.handle.net/10230/34256
• dc.language.iso eng
• dc.publisher Elsevierca
• dc.relation.ispartof Neuropharmacology. 2017 Mar 1;114:156-67
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.neuropharm.2016.11.015
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword 2-arachidonyl glycerol (2-AG)
• dc.subject.keyword Anandamide (AEA)
• dc.subject.keyword Cannabinoid
• dc.subject.keyword Fatty acid amide hydrolase (FAAH)
• dc.subject.keyword Monoacylglycerol lipase (MAGL)
• dc.subject.keyword Heroin
• dc.subject.keyword Morphine
• dc.subject.keyword Self-administration
• dc.subject.keyword Pain
• dc.title The endocannabinoid hydrolysis inhibitor SA-57: Intrinsic antinociceptive effects, augmented morphine-induced antinociception, and attenuated heroin seeking behavior in miceca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion