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Here, we show that inflammation plays a critical role in engaging the endocannabinoid system in the ventrolateral periaqueductal gray (vlPAG) to activate the descending pain modulatory circuit to inhibit pain. Inflammation-induced increases in corticosterone activate glucocorticoid receptors to increase the synthesis of 2-arachidonylglycerol (2-AG). Retrograde transmission of 2-AG stimulates presynaptic cannabinoid 1 receptors to inhibit GABA release in the vlPAG, producing anti-hyperalgesia. Conversely, blocking both glucocorticoid and cannabinoid receptor activity impairs recovery from hyperalgesia, highlighting the beneficial role of endocannabinoid signaling in pain resolution. However, this system is tightly regulated, and overstimulation of glucocorticoid receptors with corticosterone results in cannabinoid 1 receptor desensitization. In addition, cannabinoid receptors are more susceptible to desensitization in inflamed rats and rapidly desensitize in response to exogenous cannabinoid receptor agonists. Thus, there is a narrow therapeutic window for cannabinoid drugs in the context of inflammatory pain. These findings indicate that cannabinoid agonists should be used with caution in the context of inflammation to avoid CB1R desensitization, and that exploiting glucocorticoid-endocannabinoid interactions is a promising strategy to optimize cannabinoid-based therapies for inflammatory pain.<\/jats:p>","DOI":"10.1038\/s41386-026-02529-5","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T10:42:40Z","timestamp":1787136160000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Glucocorticoid\u2013endocannabinoid crosstalk in the ventrolateral periaqueductal gray (vlPAG) promotes pain resolution"],"prefix":"10.1038","author":[{"given":"Basile","family":"Coutens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-0392","authenticated-orcid":false,"given":"Courtney A.","family":"Bouchet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuliia","family":"Gvon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo C.","family":"Patti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassidy M.","family":"De Anda Gamboa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Jewett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jost","family":"Klawitter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Klawitter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary M.","family":"Heinricher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1371-8532","authenticated-orcid":false,"given":"Susan L.","family":"Ingram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"2529_CR1","unstructured":"Substance Abuse and Mental Health Services Administration. 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