Marijuana has been used for thousands of years to affect human health. Dissecting the peripheral effects from the central psychotropic effects has revealed a complex interplay between cannabinoids, endocannabinoids and their receptors. This review examines recent advances in understanding the expression, regulation and utilization of the CB(2) receptor. Here we highlight the molecular aspects of the CB(2) receptor, CB(2) receptor signaling and new ligands for this receptor. We focus in the rest of the review on recent findings in the immune system, the gastrointestinal tract and liver, the brain and the cardiovascular system and airways as examples of areas where new developments in our understanding of the CB(2) receptor have occurred. Early studies focused on expression of this receptor under baseline physiologic conditions; however, perturbations such as those that occur during inflammation, ischemia/reperfusion injury and cancer are revealing a critical role for the CB(2) receptor in regulating these disease processes amongst others. As a result, the CB(2) receptor is an appealing therapeutic target as well as a useful tool for shedding new light on physiological regulatory processes throughout the body.
"In addition to acting as agonists at CB 1 Rs (Atwood et al., 2010, 2011), JWH-018 and JWH-073 are known to bind with high affinity to CB 2 Rs, the second major cannabinoid receptor subtype (Aung et al., 2000; Chin et al., 1999). In contrast to CB 1 Rs, CB 2 Rs are expressed in highest density outside the CNS on immune cells (Klein et al., 2003) and regulate many important physiological processes ranging from inflammation to bone formation (Patel et al., 2010). Although also present in relatively low numbers in the brain and/or spinal cord, increasing evidence indicates that activation of CB 2 Rs in the CNS modulates the addictive properties of several drugs of abuse, including cocaine (Xi et al., 2011), alcohol (Onaivi et al., 2008) and nicotine (Gamaleddin et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB1Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB2Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB2Rs (hCB2Rs). The affinity of cannabinoids for hCB2Rs was determined by competition binding studies employing CHO-hCB2 membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB2 cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB2Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB2Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and ∆(9)-tetrahydrocannabinol (Δ(9)-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB2R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB2Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB2Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB1 and CB2Rs.
"CB1 are expressed at high levels in the central nervous system (CNS), whereas CB2 are found predominantly, but not exclusively, outside the CNS. CBs, together with the enzymes metabolizing AEA and 2-AG, form the endocannabinoid (EC) system , . "
[Show abstract][Hide abstract] ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of disease ranging from simple steatosis to inflammatory steatohepatitis (NASH) with different degrees of fibrosis that can ultimately progress to cirrhosis. Accumulating evidence suggests the involvement of the endocannabinoid-system in liver disease and related complications. In particular, hepatoprotective properties for Cannabinoid Receptor type 2 (CB2) have been shown both through experimental murine models of liver injury and association study between a CB2 functional variant, Q63R, and liver enzymes in Italian obese children with steatosis.
Here, in order to clarify the role of CB2 in severity of childhood NAFLD, we have investigated the association of the CB2 Q63R variant, with histological parameters of liver disease severity in 118 Italian children with histologically-proven NAFLD.
CB2 Q63R genotype was assigned performing a TaqMan assay and a general linear model analysis was used to evaluate the association between the polymorphism and the histological parameters of liver damage.
We have found that whereas CB2 Q63R variant is not associated with steatosis or fibrosis, it is associated with the severity of the inflammation (p = 0.002) and the presence of NASH (p = 0.02).
Our findings suggest a critical role for CB2 Q63R variant in modulating hepatic inflammation state in obese children and in the consequent increased predisposition of these patients to liver damage.
PLoS ONE 08/2012; 7(8):e42259. DOI:10.1371/journal.pone.0042259 · 3.23 Impact Factor
"The presence of both CB1 and CB2 receptors on immune cells , and the evidence that cannabinoids inhibit adenylyl cyclase in such cells through a pertussis toxin-sensitive mode, first suggested a role for cannabinoid receptors in the modulation of the immune system . Moreover, activation of immune cells by a range of inflammatory stimuli modulates the expression of CB1 and CB2 by these cells, a fact that has been linked to the immune-regulatory effects of cannabinoids [20, 47]. In vitro experiments have reported that cannabinoids may act as immunomodulators by (1) induction of apoptosis, (2) inhibition of cell proliferation as well as cytokine and chemokine production, and (3) expansion of regulatory T cells [48, 49]. "
[Show abstract][Hide abstract] ABSTRACT: In recent years, a growing interest has been dedicated to the study of the endocannabinoid system. The isolation of Cannabis sativa main psychotropic compound, Δ(9)-tetrahydrocannabinol (THC), has led to the discovery of an atypical neurotransmission system that modulates the release of other neurotransmitters and participates in many biological processes, including the cascade of inflammatory responses. In this context, cannabinoids have been studied for their possible therapeutic properties in neuroinflammatory diseases. In this review, historic and biochemical aspects of cannabinoids are discussed, as well as their function as modulators of inflammatory processes and therapeutic perspectives for neurodegenerative disorders, particularly, multiple sclerosis.
DNA research: an international journal for rapid publication of reports on genes and genomes 06/2012; 10(2):159-66. DOI:10.2174/157015912800604515 · 3.05 Impact Factor
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