Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists
Open accessAbstract
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.
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Co-administration of the CB2 receptor agonist JWH015 and morphine produces synergistic effects in the rat formalin model of inflammatory pain.
“Finally, co-administration of the CB 2 receptor agonist JWH015 and morphine produces synergistic effects in the rat formalin model of inflammatory pain (Grenald et al, 2016).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Grenald et al, 2016
Co-administration of the CB2 receptor agonist JWH015 and morphine produces synergistic effects in the rat SNI model of neuropathic pain.
“In addition, the co-administration of the CB 2 receptor agonist JWH015 and morphine produces synergistic effects in the rat SNI model of neuropathic pain (Grenald et al, 2016).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Grenald et al, 2016
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- Authors
- Grenald, S. A., Young, M. A., Wang, Y., Ossipov, M. H., Ibrahim, M. M., Largent-Milnes, T. M., & Vanderah, T. W.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Vanderah, Todd W.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 116
- Pages
- 59-70
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC5385155
- OpenAlex
- W2562806082
- Cited by
- 97
- References
- 64
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 9 · 2023: 14 · 2022: 5 · 2021: 14 · 2020: 15 · 2019: 10 · 2018: 8 · 2017: 5
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01CA142115)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- chronic pain, mu-opioid receptor agonists, CB2 receptor agonist, morphine, synergistic analgesia, conditioned place preference, opioid side effects, opioid sparing, inflammatory pain, postoperative pain, neuropathic pain, cannabinoid therapy
- MeSH terms
- Analgesics, Opioid, Animals, Constipation, Corpus Striatum, Disease Models, Animal, Dopamine, Dose-Response Relationship, Drug, Drug Synergism, Indoles, Male, Mice, Inbred ICR, Morphine, Reward, Rats, Sprague-Dawley, Receptors, Opioid, mu, Analgesics, Non-Narcotic, Receptor, Cannabinoid, CB2, Chronic Pain, Cannabinoid Receptor Agonists
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