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Cannabinoid CB₁ receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.

ABSTRACT: Cannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB₁ receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB₁ receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB₁ receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB₁ receptor-deficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB₁ receptor-deficient mice. Overall, this study supports a cell-autonomous role for CB₁ receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids.

SUBMITTER: Sanchez-de la Torre A

PROVIDER: S-EPMC9263142 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Cannabinoid CB<sub>1</sub> receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.

Sánchez-de la Torre Aníbal A Aguado Tania T Huerga-Gómez Alba A Santamaría Silvia S Gentile Antonietta A Chara Juan Carlos JC Matute Carlos C Monory Krisztina K Mato Susana S Guzmán Manuel M Lutz Beat B Galve-Roperh Ismael I Palazuelos Javier J

Cell death & disease 20220707 7

Cannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB<sub>1</sub> receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination ...[more]

PMID: 35798697

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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 CB₁ receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.

Publications

Cannabinoid CB<sub>1</sub> receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.

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Dataset Information

Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.

Publications

Cannabinoid CB<sub>1</sub> receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Cannabinoid CB₁ receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice.