Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Wiese BM

PROVIDER: S-EPMC8612410 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Wiese Beth M BM Liktor-Busa Erika E Levine Aidan A Couture Sarah A SA Nikas Spyros P SP Ji Lipin L Liu Yingpeng Y Mackie Kenneth K Makriyannis Alexandros A Largent-Milnes Tally M TM Vanderah Todd W TW

Cannabis and cannabinoid research 20201113 5

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. ...[more]

PMID: 33998869

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Project description:Synthetic Cannabinoids are a street drug that is widely attainable and cheap compared to natural cannabis, and has variable potency and unpredictable effects with no commercially available diagnostic test to confirm its presence. Similar to natural cannabis, Synthetic Cannabinoid intoxication can present in several ways with the most common emergency room presentations to be of neurologic and psychiatric manifestation. The respiratory depressive effect of Synthetic Cannabinoids has not been well documented in medical literature. We report four patients admitted in the Intensive Care Unit with acute respiratory failure necessitating endotracheal intubation after use of Synthetic Cannabinoid. All patients had a reversal of respiratory failure in less than 24 h, three patients had a complicated course due to aspiration pneumonia. All four patients exhibited aggressive behavior, with two of them diagnosed with Bipolar Disorder and Cocaine Use Disorder. The effect of Synthetic Cannabinoids in peripheral receptors such as chemoreceptors and baroreceptors can increase bronchial airway resistance. It is postulated that CB1 receptor stimulation could be one of the possible mechanisms of synthetic cannabinoid-induced respiratory depression. Chemical gases released after its inhalation may also cause damage to the bronchiolar epithelium and has the potential to disrupt the protective surfactant layer in the alveoli, which then could interfere with effective gas exchange leading to hypoxia and acidosis. The stimulation of CB1 receptors have a series of downstream signaling effects in the G protein-coupled pathway and mitogen-activated protein kinase (MAPK) pathway, causing suppression of both excitatory and inhibitory neuronal activity. The aforementioned molecular changes in the central nervous system after CB1 receptor stimulation could impact respiration. The use of Synthetic Cannabinoids can cause respiratory depression in individuals without an underlying pulmonary disease and adds to the growing number of literature about the presentation and debilitating adverse events from its consumption. Although there is no specific toxidrome associated with it, clinicians should have a high index of suspicion with its use especially in patients presenting with a history of drug overdose.

Project description:Introduction: Overdose fatalities associated with the opioid epidemic are predictably attributable to drug-induced respiratory depression. In terms of illicit opioid abuse, fentanyl is the synthetic opioid responsible for the largest number of overdose deaths. There is, therefore, an urgent need to identify safe and effective therapeutics that can attenuate fentanyl-induced respiratory depression. Identification of effective alternate analgesic strategies that lessen the respiratory depression associated with narcotics would also help improve current strategies for pain management. Our laboratory recently reported that the G protein-biased CB2 cannabinoid receptor agonist LY2828360 suppressed chemotherapy-induced neuropathic nociception and attenuated both morphine tolerance and physical dependence in paclitaxel-treated mice. However, the impact of LY2828360 on other undesirable side effects of opioids, such as opioid-induced respiratory depression, remains unknown. Materials and Methods: We used whole-body plethysmography to assess the impact of the CB2 cannabinoid agonist LY2828360 on fentanyl-induced respiratory depression using wild-type (WT) and CB2 knockout (CB2KO) mice. Results: Fentanyl reduced minute ventilation and respiratory frequency without altering tidal volume in both WT and CB2KO mice. In WT mice, the high dose of fentanyl (0.2 mg/kg intraperitoneal [i.p.]) produced a greater suppression of respiratory parameters compared with the low dose of fentanyl (0.1 mg/kg i.p.). Coadministration of a behaviorally active dose of LY2828360 (3 mg/kg i.p.) with fentanyl (0.2 mg/kg i.p.) attenuated fentanyl-induced respiratory depression in WT mice. Notably, LY2828360 (3 mg/kg i.p.) did not attenuate fentanyl-induced respiratory depression in CB2KO mice, consistent with mediation by CB2 receptors. Moreover, LY2828360 (3 mg/kg i.p.) alone lacked intrinsic effects on respiratory parameters in either WT or CB2KO mice. Conclusion: The combination of a CB2 agonist with fentanyl may represent a safer adjunctive therapeutic strategy compared with a narcotic analgesic alone by attenuating the development of opioid-induced respiratory depression. Moreover, the CB2 agonist, administered alone, did not alter respiration. Our findings suggest that the CB2 cannabinoid agonist LY2828360 may provide CB2-mediated protection against fentanyl-induced respiratory depression, a detrimental and unwanted side effect of opioid use and abuse.

Dataset Information

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

Publications

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

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