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Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System.

ABSTRACT: The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

SUBMITTER: Zou S

PROVIDER: S-EPMC5877694 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Project description:Cannabinoid CB(1) receptors (CB(1)Rs) mediate the effects of ?(9)-tetrahydrocannabinol (THC), the psychoactive component in marijuana. Repeated THC administration produces tolerance and dependence, which limit therapeutic development. Moreover, THC produces motor and psychoactive side effects. ?-arrestin2 mediates receptor desensitization, internalization, and signaling, but its role in these CB(1)R effects and receptor regulation is unclear.CB(1)R signaling and behaviors (antinociception, hypothermia, catalepsy) were assessed in ?-arrestin2-knockout (?arr2-KO) and wild-type mice after THC administration. Cannabinoid-stimulated [(35)S]GTP?S and [(3)H]ligand autoradiography were assessed by statistical parametric mapping and region-of-interest analysis.?-arrestin2 deletion increased CB(1)R-mediated G-protein activity in subregions of the cortex but did not affect CB(1)R binding, in vehicle-treated mice. ?arr2-KO mice exhibited enhanced acute THC-mediated antinociception and hypothermia, with no difference in catalepsy. After repeated THC administration, ?arr2-KO mice showed reduced CB(1)R desensitization and/or downregulation in cerebellum, caudal periaqueductal gray, and spinal cord and attenuated tolerance to THC-mediated antinociception. In contrast, greater desensitization was found in hypothalamus, cortex, globus pallidus, and substantia nigra of ?arr2-KO compared with wild-type mice. Enhanced tolerance to THC-induced catalepsy was observed in ?arr2-KO mice.?-arrestin2 regulation of CB(1)R signaling following acute and repeated THC administration was region-specific, and results suggest that multiple, overlapping mechanisms regulate CB(1)Rs. The observations that ?arr2-KO mice display enhanced antinociceptive responses to acute THC and decreased tolerance to the antinociceptive effects of the drug, yet enhanced tolerance to catalepsy, suggest that development of cannabinoid drugs that minimize CB(1)R interactions with ?-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression.

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Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System.

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