Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia.
| Publication Type | Academic Article |
| Authors | Martínez-Rivera A, Fetcho R, Birmingham L, Xu J, Yang R, Foord C, Scala-Chávez D, Mekawy N, Pleil K, Pickel V, Liston C, Castorena C, Levitz J, Pan Y, Briand L, Rajadhyaksha A, Lee F |
| Journal | Sci Adv |
| Volume | 10 |
| Issue | 48 |
| Pagination | eadq4779 |
| Date Published | 11/29/2024 |
| ISSN | 2375-2548 |
| Keywords | Endocannabinoids, Glycerides, Arachidonic Acids, Reward, Analgesia, Receptor, Cannabinoid, CB1, Ventral Tegmental Area, Analgesics, Opioid |
| Abstract | Converging findings have established that the endocannabinoid (eCB) system serves as a possible target for the development of new treatments as a complement to opioid-based treatments. 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's effects. Using fiber photometry with fluorescent sensors for calcium and dopamine (DA), we find that enhancing 2-AG levels diminishes opioid reward-related 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. |
| DOI | 10.1126/sciadv.adq4779 |
| PubMed ID | 39612328 |
| PubMed Central ID | PMC11606496 |