Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia
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.
Authors
- Joshua Levitz (ORCID: https://orcid.org/0000-0002-8169-6323)
- Francis S. Lee (ORCID: https://orcid.org/0000-0002-7108-9650)
- Conor Liston (ORCID: https://orcid.org/0000-0002-1639-5401)
- Ruirong Yang
- Kristen E. Pleil (ORCID: https://orcid.org/0000-0001-6300-9414)
- Robert N. Fetcho (ORCID: https://orcid.org/0000-0002-4557-4177)
- Carlos M. Castorena (ORCID: https://orcid.org/0000-0002-8576-9307)
- Arlene Martínez-Rivera (ORCID: https://orcid.org/0000-0002-4180-1635)
- Virginia M. Pickel (ORCID: https://orcid.org/0000-0001-9374-724X)
- Lisa A. Briand (ORCID: https://orcid.org/0000-0002-1228-5061)
- Anjali M. Rajadhyaksha (ORCID: https://orcid.org/0000-0002-8399-5466)
- Ying‐Xian Pan (ORCID: https://orcid.org/0000-0002-4006-8304)
- Diego Scala-Chávez
- Lizzie Birmingham
- Careen Foord
- Narmin Mekawy (ORCID: https://orcid.org/0000-0002-4629-6156)
- Jin Xu (ORCID: https://orcid.org/0000-0001-5506-4333)
Institutions
- Rutgers, The State University of New Jersey (US)
- Cornell University (US)
- MIND Research Institute (US)
- Weill Cornell Medicine (US)
- Rutgers New Jersey Medical School (US)
- Temple University (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1126/sciadv.adq4779
- Citations
- 10
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 4.48