Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease

Abstract

The identification and cloning of the two major cannabinoid (CB1 and CB2) receptors together with the discovery of their endogenous ligands in the late 80s and early 90s, resulted in a major effort aimed at understanding the mechanisms and physiological roles of the endocannabinoid system (ECS). Due to its expression and localization in the central nervous system (CNS), the CB1 receptor together with its endogenous ligands (endocannabinoids (eCB)) and the enzymes involved in their synthesis and degradation, has been implicated in multiple pathophysiological events ranging from memory deficits to neurodegenerative disorders among others. In this review, we will provide a general overview of the ECS with emphasis on the CB1 receptor in health and disease. We will describe our current understanding of the complex aspects of receptor signaling and trafficking, including the non-canonical signaling pathways such as those mediated by β-arrestins within the context of functional selectivity and ligand bias. Finally, we will highlight some of the disorders in which CB1 receptors have been implicated. Significant knowledge has been achieved over the last 30 years. However, much more research is still needed to fully understand the complex roles of the ECS, particularly in vivo and to unlock its true potential as a source of therapeutic targets.

CB 1 and CB 2 Receptor Pharmacology

“…Indeed, in a comparison between β-arrestin2 knockout mice and WT mice, distinct regional differences were observed following chronic Δ 9 -THC administration (Nguyen et al, 2012). These studies and others suggest that β-arrestin2 regulates CB 1 receptor signaling and adaptation in a central nervous system region-dependent manner (Kendall & Yudowski, 2016; Nguyen et al, 2012). …”

Computational investigation on the binding modes of Rimonabant analogs with CB1 and CB2

“…CB2 is predominantly expressed in immune system in normal situation, also expressed in central nervous system during inflammatory injury . Since CB1 and CB2 were implicated in a variety of central and peripheral physiological processes such as pain, metabolism, and neuromodulator, they have been the targets of intensive drug discovery efforts.…”

Molecular Dynamics Methodologies for Probing Cannabinoid Ligand/Receptor Interaction

“…They are expressed primarily in the CNS/immune system, respectively, and have been implicated in a variety of disease states (Kendall & Yudowski, 2016; Lu & Mackie, 2016). Modulating the behavior of the cannabinoid receptors has been the target of substantial research and the focus of significant drug discovery efforts (Vemuri & Makriyannis, 2015).…”

“…These molecules are synthesized on demand from the lipid bilayer itself. Moreover, post-activation, they are degraded by the membrane-bound enzymes fatty acid amide hydrolase and monoacylglycerol lipase, respectively (Kendall & Yudowski, 2016; Lu & Mackie, 2016; Vemuri & Makriyannis, 2015). Cannabinoid ligands are known to readily partition into the phospholipid bilayer and their orientation in the membrane has been established by a variety of methods including small-angle X-ray diffraction/differential calorimetry (Mavromoustakos, Yang, Broderick, Fournier, & Makriyannis, 1991), NMR(Kimura, Cheng, Rice, & Gawrisch, 2009; Tian, Guo, Yao, Yang, & Makriyannis, 2005), as well as simulation (Kotsikorou, Lynch, Abood, & Reggio, 2011).…”