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Here, we show in male and female mice that enhancing levels of the eCB, 2-arachidonoylglycerol (2-AG), through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL), either systemically or in the ventral tegmental area (VTA) with JZL184, leads to a substantial attenuation of the rewarding effects of opioids in mice using conditioned place preference and self-administration paradigms, without altering their analgesic properties. These effects are driven by cannabinoid receptor 1 (CB1R) within the VTA, as VTA CB1R conditional knockout counteracts JZL184\u2019s effects. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward\u2013related nucleus accumbens (NAc) activity and DA neurotransmission. Together, these findings reveal that 2-AG diminishes the rewarding properties of opioids and provides a potential adjunctive therapeutic strategy for opioid-related analgesic treatments.<\/jats:p>","DOI":"10.1126\/sciadv.adq4779","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T13:58:27Z","timestamp":1732888707000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":14,"title":["Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4180-1635","authenticated-orcid":true,"given":"Arlene","family":"Mart\u00ednez-Rivera","sequence":"first","affiliation":[{"name":"Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY 10065, USA."},{"name":"Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 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