Cannabinoid-2 Agonism with AM2301 Mitigates Morphine-Induced Respiratory Depression, Beth M. Wiese et al., 2021

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 and Todd W. Vanderah

Cannabis and Cannabinoid Research, 2021, Volume 6, Number 5, 401-412.

Doi : 10.1089/can.2020.0076



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 preBo¨ tzinger 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 (D9-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



Accidental overdose fatalities define the opioid epidemic despite alternative pain and opioid use disorder therapies.1,2 The U.S. Centers for Disease Control report 400,000 overdose deaths total with nearly 190 people dying daily.3 Respiratory depression is often the cause of death in opioid overdose that can be mitigated by opioid receptor antagonism with naloxone.4 Yet, adequate access and administration of naloxone to patients remains challenging.1,5,6 Therefore, identifying novel therapeutic strategies to prevent opioid-induced respiratory depression is vital.

Cannabinoids are analgesic in several models of pain5,7–11 and act synergistically with opioids,12 allowing for opioid sparing. Medicinal cannabis patients cite pain relief and opioid replacement as top reasons for use.13 Although cannabinoid-1 receptor (CB1R) activation induces pain relief and increases patient quality of life, agonists are associated with psychoactivity.14 In contrast, preclinical studies report that cannabinoid-2 receptor (CB2R) agonism reduces acute, chronic, and inflammatory pain without psychoactive side effects.8–11

However, the actions of cannabinoid compounds on respiration
and interactions with opioid respiratory depression are unknown.
Studies here evaluated how cannabinoids influence respiratory function. Whole body plethysmography was performed after dosing with CB1R/CB2R agonists alone and in combination with morphine sulfate (MS) suggested that activation of CB2R is sufficient to assuage MS-induced respiratory depression, whereas selective CB1R activation suppressed respiration.