Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists

Neuropharmacology. 2017 Apr:116:59-70. doi: 10.1016/j.neuropharm.2016.12.008. Epub 2016 Dec 20.

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.

Keywords: Antinociception; CB2 cannabinoid receptor agonist; Cocaine hydrochloride (PubChem CID: 656832); Inflammation; JWH015 (PubChem CID: 4273754); Morphine; Morphine hydrochloride (PubChem CID: 5464110); Reward; Synergy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Non-Narcotic / pharmacology*
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Cannabinoid Receptor Agonists / pharmacology*
  • Chronic Pain / drug therapy*
  • Chronic Pain / metabolism
  • Constipation / chemically induced
  • Constipation / drug therapy
  • Constipation / metabolism
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Indoles / pharmacology*
  • Male
  • Mice, Inbred ICR
  • Morphine / adverse effects
  • Morphine / pharmacology*
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB2 / agonists
  • Receptor, Cannabinoid, CB2 / metabolism
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism
  • Reward

Substances

  • Analgesics, Non-Narcotic
  • Analgesics, Opioid
  • Cannabinoid Receptor Agonists
  • Cnr2 protein, mouse
  • Cnr2 protein, rat
  • Indoles
  • Receptor, Cannabinoid, CB2
  • Receptors, Opioid, mu
  • Morphine
  • Dopamine
  • JHW 015