Cited by 795Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsNeuropeptides and Animal Physiology

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An endocannabinoid mechanism for stress-induced analgesia

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Hohmann, Andrea G., Suplita, Richard L., Bolton, Nathan M., Neely, Mark H., Fegley, Darren, Mangieri, Regina, Krey, Jocelyn F., Michael Walker, J., Holmes, Philip V., Crystal, Jonathon D., Duranti, Andrea, Tontini, Andrea, Mor, Marco, Tarzia, Giorgio, Piomelli, Daniele·2005·Nature

DOI 10.1038/nature03658

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Abstract

Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB(1) receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol (2-AG) and anandamide. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase, which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.

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Authors: Hohmann, A. G., Suplita, R. L., Bolton, N. M., Neely, M. H., Fegley, D., Mangieri, R., Krey, J. F., Michael Walker, J., Holmes, P. V., Crystal, J. D., Duranti, A., Tontini, A., Mor, M., Tarzia, G., & Piomelli, D.
Affiliations: University of Georgia (US)
University of California, Irvine (US)
Brown University (US)
University of Urbino (IT)
University of Parma (IT)
Corresponding author: Hohmann, Andrea G.
Piomelli, Daniele
ORCID: Hohmann, Andrea G.
Bolton, Nathan M.
Mangieri, Regina
Krey, Jocelyn F.
Holmes, Philip V.
Crystal, Jonathon D.
Duranti, Andrea
Tontini, Andrea
Mor, Marco
Piomelli, Daniele
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2005-06
Volume: 435
Issue: 7045
Pages: 1108-1112
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03658
OpenAlex: W2030777873
Cited by: 778
References: 30
Citations by year: 2026: 14 · 2025: 24 · 2024: 22 · 2023: 22 · 2022: 28 · 2021: 26 · 2020: 22 · 2019: 20 · 2018: 29 · 2017: 53 · 2016: 34 · 2015: 38 · 2014: 40 · 2013: 33 · 2012: 45
FWCI: 39.98
Type: journal article
Language: en
Open access: green
escholarship.org
Licence: cc-by
www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by)
CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords: stress-induced analgesia, endocannabinoid system, CB1 receptor, periaqueductal gray, 2-arachidonoylglycerol, anandamide, monoacylglycerol lipase, fatty acid amide hydrolase, opioid-independent analgesia, pain inhibition, stress-related disorders, therapeutic target
MeSH terms: Analgesia, Animals, Arachidonic Acids, Biological Transport, Biphenyl Compounds, Glycerides, Hydrolysis, Male, Mesencephalon, Monoacylglycerol Lipases, Stress, Physiological, Rats, Sprague-Dawley, Rats, Wistar, Receptor, Cannabinoid, CB1, Rats, Polyunsaturated Alkamides, Cannabinoid Receptor Modulators, Endocannabinoids, In Vitro Techniques

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An endocannabinoid mechanism for stress-induced analgesia

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