CB 2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids
Open accessAbstract
CB 2 cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB 2 receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB 2 receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB 2 receptor-mediated inhibition of pain responses. Here, we test the hypothesis that CB 2 receptor activation stimulates release from keratinocytes of the endogenous opioid β-endorphin, which then acts at opioid receptors on primary afferent neurons to inhibit nociception. The antinociceptive effects of the CB 2 receptor-selective agonist AM1241 were prevented in rats when naloxone or antiserum to β-endorphin was injected in the hindpaw where the noxious thermal stimulus was applied, suggesting that β-endorphin is necessary for CB 2 receptor-mediated antinociception. Further, AM1241 did not inhibit nociception in μ-opioid receptor-deficient mice. Hindpaw injection of β-endorphin was sufficient to produce antinociception. AM1241 stimulated β-endorphin release from rat skin tissue and from cultured human keratinocytes. This stimulation was prevented by AM630, a CB 2 cannabinoid receptor-selective antagonist and was not observed in skin from CB 2 cannabinoid receptor-deficient mice. These data suggest that CB 2 receptor activation stimulates release from keratinocytes of β-endorphin, which acts at local neuronal μ-opioid receptors to inhibit nociception. Supporting this possibility, CB 2 immunolabeling was detected on β-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of β-endorphin, where CB 2 receptors are present, leading to anatomical specificity of opioid effects.
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In the periphery, CB2 receptor agonists lead to endorphin release from keratinocytes.
“In the periphery, CB 2 receptor agonists lead to endorphin release from keratinocytes (Ibrahim et al, 2005).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Ibrahim et al, 2005
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- Authors
- Ibrahim, M. M., Porreca, F., Lai, J., Albrecht, P. J., Rice, F. L., Khodorova, A., Davar, G., Makriyannis, A., Vanderah, T. W., Mata, H. P., & Malan, T. P.
- Affiliations
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-02-10
- Volume
- 102
- Issue
- 8
- Pages
- 3093-3098
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC549497
- OpenAlex
- W2039106853
- Cited by
- 521
- References
- 33
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 8 · 2023: 18 · 2022: 21 · 2021: 23 · 2020: 22 · 2019: 15 · 2018: 13 · 2017: 29 · 2016: 16 · 2015: 19 · 2014: 19 · 2013: 31 · 2012: 29
- FWCI
- 27.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (DA015866, R01DA015866)
- National Institute of Neurological Disorders and Stroke (NS 34692, R01NS034692)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- CB2 receptor, antinociception, beta-endorphin, endogenous opioids, keratinocytes, mu-opioid receptor, AM1241, AM630, nociception, stratum granulosum, pain modulation, naloxone
- MeSH terms
- Analgesics, Animals, beta-Endorphin, Cannabinoids, Cells, Cultured, Humans, Male, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB2, Receptor, Endothelin B, Rats
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