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

Shaness A. Grenald, Madison A. Young, Yue Wang, Michael H. Ossipov, Mohab M. Ibrahim, Tally M. Largent-Milnes, Todd W Vanderah

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)59-70
Number of pages12
JournalNeuropharmacology
Volume116
DOIs
StatePublished - Apr 1 2017

Fingerprint

Cannabinoid Receptor Agonists
mu Opioid Receptor
Chronic Pain
Opioid Analgesics
Gastrointestinal Transit
Morphine
Neuralgia
Pain
Opiate Alkaloids
Cannabinoid Receptor CB2
Nociceptive Pain
Cannabinoid Receptors
Non-Steroidal Anti-Inflammatory Agents
Acetaminophen
Nicotine
Reward
Cocaine
Prescriptions
Analgesics
Rodentia

Keywords

  • Antinociception
  • CB2 cannabinoid receptor agonist
  • Inflammation
  • Morphine
  • Reward
  • Synergy

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Grenald, S. A., Young, M. A., Wang, Y., Ossipov, M. H., Ibrahim, M. M., Largent-Milnes, T. M., & Vanderah, T. W. (2017). Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology, 116, 59-70. https://doi.org/10.1016/j.neuropharm.2016.12.008

Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. / Grenald, Shaness A.; Young, Madison A.; Wang, Yue; Ossipov, Michael H.; Ibrahim, Mohab M.; Largent-Milnes, Tally M.; Vanderah, Todd W.

In: Neuropharmacology, Vol. 116, 01.04.2017, p. 59-70.

Research output: Contribution to journalArticle

Grenald SA, Young MA, Wang Y, Ossipov MH, Ibrahim MM, Largent-Milnes TM et al. Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology. 2017 Apr 1;116:59-70. https://doi.org/10.1016/j.neuropharm.2016.12.008
Grenald, Shaness A. ; Young, Madison A. ; Wang, Yue ; Ossipov, Michael H. ; Ibrahim, Mohab M. ; Largent-Milnes, Tally M. ; Vanderah, Todd W. / Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. In: Neuropharmacology. 2017 ; Vol. 116. pp. 59-70.
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