Cannabinoid CB(2) receptors in health and disease.
Snyder Institute of Infection, Immunity & Inflammation, Department of Physiology and Pharmacology, University of Calgary, Canada.Current Medicinal Chemistry (Impact Factor: 3.85). 02/2010; 17(14):1393-410.
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.
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- "Some SCB metabolites retain affinity and activity for CB2Rs, the second major cannabinoid receptor subtype Although the abuse potential of SCBs, such as JWH-018 and JWH- 073, likely results from agonist action at CB1Rs, most SCBs present in K2 also have high affinity and significant activity at the second major cannabinoid receptor subtype, CB2Rs (Aung et al., 2000; Chin et al., 1999). Unlike CB1Rs, CB2Rs are most abundantly found on immune cells outside the CNS (Klein et al., 2003) and regulate a range of physiological processes from inflammation to bone formation (Patel et al., 2010). However, in preclinical models, activation of low numbers of CB2Rs in the CNS has also been shown to modulate the abuse-related properties of several drugs of abuse such as alcohol (Onaivi et al., 2008), nicotine (Gamaleddin et al., 2012) and cocaine (Xi et al., 2011). "
ABSTRACT: K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances.
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- "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). "
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.
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- "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 , . "
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.
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