Cannabinoid CB2 receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear

Ivy, Devon; Palese, Francesca; Vozella, Valentina; Fotio, Yannick; Yalcin, Aylin; Ramirez, Gina L; Mears, David; Wynn, Gary H.; Piomelli, Daniele

doi:10.1038/s41386-020-0696-x

Cited by 33 publications

(25 citation statements)

References 56 publications

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“…A multiple comparisons two-way ANOVA was utilized to evaluate multiple inverse agonists for a factor of drug (F[4,74] = 13.86, p < 0.0001). Respiratory depression was induced by AM630 10 mg/kg, 35,36 (N = 7) under the 5% CO 2 , p = 0.0328, but not under room air, p = 0.2444. The inverse agonist, SR-144528, at 10 mg/ kg induced respiratory depression on its own (N = 8) in room air p = 0.0012 and 5% CO 2 p = 0.0315.…”

Section: Actions Of Cb Inverse Agonists On Respiratory Depressionmentioning

confidence: 90%

“…6E); administration of SR-144528 10 mg/kg 10 min before the administration of vehicle, AM2301 10 mg/kg, or AM230110 mg/kg + MS 10 mg/kg was conducted ( Fig. 6G) and an interaction was seen between the effects of drug and time (F [35,352] = 14.70, p < 0.0001) that prevented the reversal of hypersensitivity by AM2301 alone, p > 0.9999 at all time points, but had no impact on vehicle, p > 0.9999 at all time points, or AM2301 + MS combination, p < 0.0001 at all time points, administration throughout the time course (Fig. 6G, H).…”

Section: Evaluation Of Postoperative Pain After Am2301 + Ms Administrmentioning

confidence: 99%

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

Wiese

Liktor‐Busa

Levine

et al. 2020

Cannabis and Cannabinoid Research

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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 preBö 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 (D 9-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.

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Section: Actions Of Cb Inverse Agonists On Respiratory Depressionmentioning

confidence: 90%

Section: Evaluation Of Postoperative Pain After Am2301 + Ms Administrmentioning

confidence: 99%

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

Wiese

Liktor‐Busa

Levine

et al. 2020

Cannabis and Cannabinoid Research

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“…There is an ongoing clinical trial sponsored by Zynerba Pharmaceuticals, where the efficacy of their CBD gel is being tested on 22QS minors. Due to the commonalities shared by ASD, FXS, and 22QS, the rationale is that CBD would exert anxiolytic and behavioural improvements, resembling those observed in CBD therapy of ASD and FXS (4,45).…”

Section: Cannabinoids As Potentially Therapeutic For Paediatric Psychiatric Disordersmentioning

confidence: 99%

Cannabidiol and Neurodevelopmental Disorders in Children

2021

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Neurodevelopmental and neuropsychiatric disorders (such as autism spectrum disorder) have broad health implications for children, with no definitive cure for the vast majority of them. However, recently medicinal cannabis has been successfully trialled as a treatment to manage many of the patients' symptoms and improve quality of life. The cannabinoid cannabidiol, in particular, has been reported to be safe and well-tolerated with a plethora of anticonvulsant, anxiolytic and anti-inflammatory properties. Lately, the current consensus is that the endocannabinoid system is a crucial factor in neural development and health; research has found evidence that there are a multitude of signalling pathways involving neurotransmitters and the endocannabinoid system by which cannabinoids could potentially exert their therapeutic effects. A better understanding of the cannabinoids' mechanisms of action should lead to improved treatments for neurodevelopmental disorders.

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“…Although there has been no study showing CB2 involvement in the antidepressant effect mediated by 2‐AG, a recent publication by Ivy and colleagues supports its involvement 59 . The authors demonstrated that animals submitted to TMT, an innately aversive substance that produces fear behaviour and long‐lasting anxiety‐like behaviour, had their behaviour reverted/normalized by the MAGL inhibitor administration 59 . Moreover, this anxiolytic‐like effect was not mediated by CB1 but through CB2 receptors 59 .…”

Section: Mechanisms Of 2‐ag Signalling In Stress and Depressionmentioning

confidence: 99%

“…The authors demonstrated that animals submitted to TMT, an innately aversive substance that produces fear behaviour and long‐lasting anxiety‐like behaviour, had their behaviour reverted/normalized by the MAGL inhibitor administration 59 . Moreover, this anxiolytic‐like effect was not mediated by CB1 but through CB2 receptors 59 . Since anxiolytic and antidepressant‐like effects share many common mechanisms in limbic regions, this recent evidence can support the possibility of CB2 receptors as a target for antidepressant‐like effect of 2‐AG.…”

Section: Mechanisms Of 2‐ag Signalling In Stress and Depressionmentioning

confidence: 99%

Targeting 2‐arachidonoylglycerol signalling in the neurobiology and treatment of depression

Silveira

Wegener

Joca

2021

Basic Clin Pharma Tox

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The endocannabinoid 2‐arachidonoylglycerol (2‐AG) is an atypical neurotransmitter synthesized on demand in response to a wide range of stimuli, including exposure to stress. Through the activation of cannabinoid receptors, 2‐AG can interfere with excitatory and inhibitory neurotransmission in different brain regions and modulate behavioural, endocrine and emotional components of the stress response. Exposure to chronic or intense unpredictable stress predisposes to maladaptive behaviour and is one of the main risk factors involved in developing mood disorders, such as major depressive disorder (MDD). In this review, we describe the molecular mechanisms involved in 2‐AG signalling in the brain of healthy and stressed animals and discuss how such mechanisms could modulate stress adaptation and susceptibility to depression. Furthermore, we review preclinical evidence indicating that the pharmacological modulation of 2‐AG signalling stands as a potential new therapeutic target in treating MDD. Particular emphasis is given to the pharmacological augmentation of 2‐AG levels by monoacylglycerol lipase (MAGL) inhibitors and the modulation of CB2 receptors.

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Cannabinoid CB2 receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear

Cited by 33 publications

References 56 publications

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

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

Cannabidiol and Neurodevelopmental Disorders in Children

Targeting 2‐arachidonoylglycerol signalling in the neurobiology and treatment of depression

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