Cannabinoid-2 Agonism with AM2301 Mitigates Morphine-Induced Respiratory Depression

Cannabis Cannabinoid Res. 2021 Oct;6(5):401-412. doi: 10.1089/can.2020.0076. Epub 2020 Nov 13.


Introduction: An escalating number of fatalities resulting from accidental opioid overdoses typically attributed to respiratory depression continue to define the opioid epidemic. Opioid respiratory depression results from a decrease in reflexive inspiration within the preBötzinger complex in the brainstem. Objective: Cannabinoid receptor agonism is reported to enhance opioid analgesia, yet whether cannabinoids enhance or inhibit opioid-induced respiratory depression is unknown. Methods: Studies herein sought to define the roles of cannabinoid-1 receptor (CB1R) and cannabinoid-2 receptor (CB2R) on respiratory depression using selective agonists alone and in combination with morphine in male mice. Results: Using whole body plethysmography, the nonselective CB1R and CB2R agonist (Δ9-tetrahydrocannabinol) and the CB1R synthetic cannabinoid, AM356, induced respiratory depression, whereas the well-published selective CB2 agonist, JWH 133, and the novel CB2 agonist (AM2301) did not. Moreover, a selective CB2R agonist (AM2301) significantly attenuated morphine sulfate-induced respiratory depression. Conclusion: Notably, findings suggest that attenuation of opioid-induced respiratory depression relies on CB2R activation, supporting selective CB2R agonism as an opioid adjunct therapy.

Keywords: cannabinoid receptor 1; cannabinoid receptor 2; mu opioid receptor; opioid-induced respiratory depression; preBötzinger complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / adverse effects
  • Animals
  • Cannabinoid Receptor Agonists / pharmacology
  • Cannabinoids*
  • Male
  • Mice
  • Morphine / adverse effects
  • Respiratory Insufficiency* / chemically induced


  • Analgesics, Opioid
  • Cannabinoid Receptor Agonists
  • Cannabinoids
  • Morphine