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.

Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia