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

Beth M. Wiese, Erika Liktor-Busa, Aidan Levine, Sarah A. Couture, Spyros P. Nikas, Lipin Ji, Yingpeng Liu, Kenneth MacKie, Alexandros Makriyannis, Tally M. Largent-Milnes, Todd W. Vanderah

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)401-412
Number of pages12
JournalCannabis and Cannabinoid Research
Issue number5
StatePublished - Oct 2021


  • Cannabinoid receptor 1
  • Cannabinoid receptor 2
  • Mu opioid receptor
  • Opioid-induced respiratory depression
  • Prebötzinger complex

ASJC Scopus subject areas

  • Pharmacology
  • Complementary and alternative medicine
  • Pharmacology (medical)


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