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Cannabidiol regulates behavioural alterations and gene expression changes induced by spontaneous cannabinoid withdrawal.

ABSTRACT: BACKGROUND AND PURPOSE:Cannabidiol (CBD) represents a promising therapeutic tool for treating cannabis use disorder (CUD). This study aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous cannabinoid withdrawal. EXPERIMENTAL APPROACH:Spontaneous cannabinoid withdrawal was evaluated 12 h after cessation of CP-55,940 treatment (0.5 mg·kg-1 every 12 h, i.p.; 7 days) in C57BL/6J mice. The effects of CBD (5, 10 and 20 mg·kg-1 , i.p.) on withdrawal-related behavioural signs were evaluated by measuring motor activity, somatic signs and anxiety-like behaviour. Furthermore, gene expression changes in TH in the ventral tegmental area, and in the opioid ? receptor (Oprm1), cannabinoid CB1 receptor (Cnr1) and CB2 receptor (Cnr2) in the nucleus accumbens, were also evaluated using the real-time PCR technique. KEY RESULTS:The administration of CBD significantly blocked the increase in motor activity and the increased number of rearings, rubbings and jumpings associated with cannabinoid withdrawal, and it normalized the decrease in the number of groomings. However, CBD did not change somatic signs in vehicle-treated animals. In addition, the anxiogenic-like effect observed in abstinent mice disappeared with CBD administration, whereas CBD induced an anxiolytic-like effect in non-abstinent animals. Moreover, CBD normalized gene expression changes induced by CP-55,940-mediated spontaneous withdrawal. CONCLUSIONS AND IMPLICATIONS:The results suggest that CBD alleviates spontaneous cannabinoid withdrawal and normalizes associated gene expression changes. Future studies are needed to determine the relevance of CBD as a potential therapeutic tool for treating CUD.

SUBMITTER: Navarrete F

PROVIDER: S-EPMC6003647 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Cannabidiol regulates behavioural alterations and gene expression changes induced by spontaneous cannabinoid withdrawal.

Navarrete Francisco F Aracil-Fernández Auxiliadora A Manzanares Jorge J

British journal of pharmacology 20180503 13

<h4>Background and purpose</h4>Cannabidiol (CBD) represents a promising therapeutic tool for treating cannabis use disorder (CUD). This study aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous cannabinoid withdrawal.<h4>Experimental approach</h4>Spontaneous cannabinoid withdrawal was evaluated 12 h after cessation of CP-55,940 treatment (0.5 mg·kg<sup>-1</sup> every 12 h, i.p.; 7 days) in C57BL/6J mice. The effects of CBD (5, 10 and 20 ...[more]

PMID: 29624642

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Project description:Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as ?(9)-tetrahydrocannabinol (?(9)-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown.We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid ?(9)-THC. We also explored the site and possible mechanism of action of AM1710.Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB1KO, CB2KO, and WT mice. Both AM1710 and ?(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to ?(9)-THC, chronic administration of AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB2KO mice and WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-? and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice.Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.

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Cannabidiol regulates behavioural alterations and gene expression changes induced by spontaneous cannabinoid withdrawal.

Publications

Cannabidiol regulates behavioural alterations and gene expression changes induced by spontaneous cannabinoid withdrawal.

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