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

Sci Adv. 2024 Nov 29;10(48):eadq4779. doi: 10.1126/sciadv.adq4779. Epub 2024 Nov 29.

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.

MeSH terms

  • Analgesia* / methods
  • Analgesics, Opioid* / pharmacology
  • Animals
  • Arachidonic Acids* / metabolism
  • Benzodioxoles / pharmacology
  • Dopamine / metabolism
  • Endocannabinoids* / metabolism
  • Female
  • Glycerides* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monoacylglycerol Lipases / antagonists & inhibitors
  • Monoacylglycerol Lipases / metabolism
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Piperidines / pharmacology
  • Receptor, Cannabinoid, CB1* / metabolism
  • Reward*
  • Ventral Tegmental Area* / drug effects
  • Ventral Tegmental Area* / metabolism

Substances

  • Endocannabinoids
  • Glycerides
  • glyceryl 2-arachidonate
  • Arachidonic Acids
  • Receptor, Cannabinoid, CB1
  • Analgesics, Opioid
  • Monoacylglycerol Lipases
  • Piperidines
  • JZL 184
  • Benzodioxoles
  • Dopamine