title: Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists.
abstract: The misuse of prescription opiates is on the rise with combination therapies (e.g. acetaminophen or NSAIDs) resulting in severe liver and kidney damage. In recent years, cannabinoid receptors have been identified as potential modulators of pain and rewarding behaviors associated with cocaine, nicotine and ethanol in preclinical models. Yet, few studies have identified whether mu opioid agonists and CB2 agonists act synergistically to inhibit chronic pain while reducing unwanted side effects including reward liability. We determined if analgesic synergy exists between the mu-opioid agonist morphine and the selective CB2 agonist, JWH015, in rodent models of acute and chronic inflammatory, post-operative, and neuropathic pain using isobolographic analysis. We also investigated if the MOR-CB2 agonist combination decreased morphine-induced conditioned place preference (CPP) and slowing of gastrointestinal transit. Co-administration of morphine with JWH015 synergistically inhibited preclinical inflammatory, post-operative and neuropathic-pain in a dose- and time-dependent manner; no synergy was observed for nociceptive pain. Opioid-induced side effects of impaired gastrointestinal transit and CPP were significantly reduced in the presence of JWH015. Here we show that MOR + CB2 agonism results in a significant synergistic inhibition of preclinical pain while significantly reducing opioid-induced unwanted side effects. The opioid sparing effect of CB2 receptor agonism strongly supports the advancement of a MOR-CB2 agonist combinatorial pain therapy for clinical trials.
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona Tucson, AZ 85724, United States.
authors.forename: Shaness A
authors.initials: SA
authors.lastname: Grenald
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona Tucson, AZ 85724, United States.
authors.forename: Madison A
authors.initials: MA
authors.lastname: Young
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona Tucson, AZ 85724, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona Tucson, AZ 85724, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona Tucson, AZ 85724, United States.
authors.forename: Mohab M
authors.initials: MM
authors.lastname: Ibrahim
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona Tucson, AZ 85724, United States.
authors.forename: Tally M
authors.initials: TM
authors.lastname: Largent-Milnes
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona Tucson, AZ 85724, United States. Electronic address: Vanderah@email.arizona.edu.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D059350:Chronic Pain / Q000188:drug therapy* / Q000378:metabolism; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008813:Mice, Inbred ICR; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D012201:Reward
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D063386:Cannabinoid Receptor Agonists; C571431:Cnr2 protein, mouse; C469526:Cnr2 protein, rat; D007211:Indoles; D043885:Receptor, Cannabinoid, CB2; D017450:Receptors, Opioid, mu; D009020:Morphine; D004298:Dopamine; C402944:JHW 015
keywords: Antinociception; CB2 cannabinoid receptor agonist; Cocaine hydrochloride (PubChem CID: 656832); Inflammation; JWH015 (PubChem CID: 4273754); Morphine; Morphine hydrochloride (PubChem CID: 5464110); Reward; Synergy