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And Synthetic-Cannabinoids and the Cannabinoid-Induced Hyperemesis GASTRO ISSN 2377-8369 http://dx.doi.org/10.17140/GOJ-SE-1-101 Open Journal Special Edition “Comorbidity Investigations of Endo- Phyto- and Synthetic-Cannabinoids Gastrointestinal Disorders with Mental Disorders” and the Cannabinoid-Induced Review Hyperemesis Syndrome *Corresponding author * Nissar A. Darmani, PhD Nissar A. Darmani, PhD ; Weixia Zhong, PhD Professor of Pharmacology Associate Dean for Basic Medical Sciences and Research Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Department of Basic Medical Sciences Western University of Health Sciences, Pomona, CA 91766, USA College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street Pomona, CA 91766, USA ABSTRACT Tel. 1 909 469 5654; (909) 469-5218 Fax: 1 909 469 5577 E-mail: [email protected] In this short review, the current status of the endocannabinoid system (ECS) and the major cannabinoids produced in humans/animals (endocannabinoids), plants (phytocannabinoids), and those manufactured in the laboratory (synthetic cannabinoids) will be elucidated. Synthetic and Special Edition 1 phytocannabinoids produce their psychoactive effects (e.g., euphoria, altered perceptions) via Article Ref. #: 1000GOJSE1101 the activation of cannabinoids CB1 receptors (CB1Rs). To date there is no report to demonstrate that administration of endocannabinoids can induce euphoria in humans. A key indication for Article History use of phyto- and synthetic cannabinoids in the clinic is for the prevention of chemotherapy- Received: August 10th, 2016 induced nausea and vomiting. However, the major psychoactive component of the marijuana 9 Accepted: September 20th, 2017 plant, delta-9-tetrahydrocannabinol (Δ -THC), as well as synthetic cannabinoid may also evoke Published: September 21st, 2017 vomiting in some patients. In this review, we further discuss these gastrointestinal side-effects of cannabinoids which in some patients may lead to a more serious gastrointestinal condition known as the cannabinoid-induced hyperemesis syndrome (CHS). Lastly, we debate the Citation potential mechanisms underlying CHS and its prevention. Darmani NA, Zhong W. Endo- phy- to- and synthetic-cannabinoids and the cannabinoid-induced hypereme- KEY WORDS: Cannabinoid-induced hyperemesis syndrome (CHS); Endocannabinoid system sis syndrome. Gastro Open J. 2017; (ECS); Synthetic-cannabinoids; Cannabis sativa. SE(1): S1-S8. doi: 10.17140/GOJ- SE-1-101 9 ABBEVIATIONS: ECS: Endocannabinoid system; CB1Rs: CB1 Receptors; Δ -THC: Delta- 9-tetrahydrocannabinol; CHS: Cannabinoid-Induced Hyperemesis Syndrome; CB2R: CB2- Receptors; Anandamide: Arachidonoyl ethanolamide; 2-AG: 2-Arachidonoylglycerol; NADA: N-arachidonoyl dopamine; OAE: Virodhamine; SCBs: Synthetic Cannabinoids; ECS: The Endocannabinoid System; PI: Phosphoinositol; PLC: Phospholipase C; DAG: Diacylglycerol; DAGL: Diacylglycerol lipase; NAPE: N-arachidonoyl phosphatidylethanolamine; NAPE-PLD: N-acylphosphatidylethanolamine-hydrolyzing phospholipase D; FAAH: Fatty Acid Amide Hydrolase; CINV: Chemotherapy-Induced Nausea and Vomiting; CBD: Cannabidiol; DAWN: Drug Abuse Warning Network; CVS: Cyclic-Type Vomiting Syndrome; IBS: Irritable Bowel Syndrome; IBD: Inflammatory Bowel Disease; TRPV1: Transient Receptor Potential Vanilloid 1. INTRODUCTION The Endocannabinoid System Cannabis refers to constituents of the plant Cannabis sativa, commonly known as marijuana. Copyright Cannabis has been used medically for thousands of years in Asian and Middle Eastern coun- ©2017 Darmani NA. This is an tries.1 During the mid-19th century, cannabis preparations were introduced in Europe and the open access article distributed un- 2 2 der the Creative Commons Attribu- United States. Basic laboratory research on cannabis started in 1940’s leading to the isolation tion 4.0 International License (CC and chemical characterization of the major psychoactive constituent of marijuana plant, delta- BY 4.0), which permits unrestricted 9-tetrahydrocannabinol (Δ9-THC) in 1964.1 The pharmacological effects of Δ9-THC can vary use, distribution, and reproduction with dose, route of administration, user experience, and the setting of use. Marijuana intoxica- in any medium, provided the origi- nal work is properly cited. tion can produce “a high” as well as changes in mood, perception and motivation. Gastro Open J Page S1 GASTRO Open Journal ISSN 2377-8369 http://dx.doi.org/10.17140/GOJ-SE-1-101 The development of novel and potent analogs of Δ9- lated with either an increase in intracellular Ca2+, or following THC played a major role in the characterization and cloning of metabotropic receptor activation involving Gq/11 or possibly Gs 4-5 cannabinoid CB1- and CB2-receptors (CB1R and CB2R) in 1990 proteins. These ligands are found both in the brain and in the and 1993, respectively.3 The above discussed psychoactive ef- periphery, for example, in the gastrointestinal tract, where they 9 fects of Δ -THC are mediated via CB1Rs in the brain. CB1R act on cannabinoid and other receptors. The most important and CB2R are members of the subfamily of G-protein-coupled pathway for the synthesis of 2-AG begins with the activation receptors and predominantly couple to Gi/o to produce multiple of a phosphoinositol (PI)-phospholipase C (PLC) which hydro- cellular effects including inhibition of adenylate cyclase and lyzes inositol phospholipids at the sn-2 position, producing dia- regulation of voltage-gated calcium channels, regulation of po- cylglycerol (DAG). The hydrolysis of DAG via sn-1-selective 3-4 tassium currents, and increase of calcium influxvia Gs and Gq. diacylglycerol lipases (DAGL)-a and DAGL-b then leads to CB1R is considered the most abundant metabotropic receptor in the formation of 2-AG. Alternatively, but less well character- the brain and is distributed throughout the central and peripheral ized, is the sequential hydrolysis of PI by phospholipase A1 to nervous system. CB1Rs are frequently expressed in high density make lyso-PI which is then further hydrolyzed to 2-AG by lyso on presynaptic nerve terminals of both inhibitory and excitatory PI-specific PLC. The metabolism of 2-AG appears to be com- nerves. Activation of presynaptic CB1Rs is postulated to sup- plex and probably involves enzymatic oxygenation, acylation, press neurotransmission by decreasing Ca2+ influx through high or phosphorylation; but the most important pathway for 2-AG 2+ 3 4-5 voltage-gated Ca channels. CB2Rs are mainly expressed on metabolism is hydrolysis. cells and organs of the immune system and modulate their func- tion, but they are also found in the brain and at other sites in the An important route of anandamide synthesis begins body. The discovery of CBRs was soon followed in 1992 and with the membrane phospholipid precursor, N-arachidonoyl 1995 by the demonstration of the existence of endogenous CBR phosphatidylethanolamine (NAPE), which is formed by the agonists such as arachidonoyl ethanolamide (anandamide) and transfer of arachidonic acid from the sn-1 position of a donor 2-arachidonoylglycerol (2-AG).4 While anandamide and 2-AG phospholipid to phosphatidylethanolamine by N-acyltransfer- are among the well-studied endocannabinoids, other potential ase.4-5 Hydrolysis of NAPE by an N-acylphosphatidylethanol- endocannabinoids may include 2-arachidonylglyceryl ether amine-hydrolyzing phospholipase D (NAPE-PLD) produces (noladin ether), N-arachidonoyl dopamine (NADA) and virod- anandamide. Additional enzymatic pathways for the produc- hamine (OAE). Although, the term ‘cannabinoid’ was originally tion of anandamide also exists via the sequential deacylation of used to refer to a number of structurally related C21 aromatic NAPE by the enzyme alpha beta-hydrolase 4 and the cleavage of hydrocarbon compounds isolated from the plant Cannabis sa- glycerophosphate to yield anandamide, and a PLC-mediated hy- tiva, today it refers to any ligand that binds to and modulates drolysis of NAPE which produces phosphoanandamide, which the activity of CBRs. Thus, cannabinoids are structurally diverse is then dephosphorylated to produce anandamide. The principal (Figure 1) and range from compounds that are endogenously enzyme for the degradation of anandamide is fatty acid amide produced (endocannabinoids) to plant-derived (phytocannabi- hydrolase (FAAH). noids) and synthesized compounds (SCBs). The endocannabi- noid system (ECS) is composed of CBRs, endocannabinoids and The cannabis plant synthesizes at least 400 chemicals the enzymes involved in their synthesis. of which more than 60 are structurally related to Δ9-THC. Today, several hundred cannabinoid agonists, antagonists, and inverse Unlike many preformed intercellular mediators, en- agonists, including active and inactive metabolites, and related docannabinoids are made on demand when cells are stimu- structures are available.3 Cannabinoid agonists can be classified Figure 1: The Comparative Structures of Delta-9-Tetrahydrocannabinol (Δ9-THC), Anandamide, 2-AG and a Synthetic cannabinoid JWH-018 and the CB1R Antagonist SR 141716A. Gastro Open J Page S2 GASTRO Open Journal ISSN 2377-8369 http://dx.doi.org/10.17140/GOJ-SE-1-101 according to their chemical structure into four main groups.3 The and/or metabolism of endocannabinoids. However, thus far and first of these is the “classical cannabinoid” group which is made unlike animal studies,12 available clinical findings have failed to of dibenzopyran derivatives and includes Δ9-THC and HU-210. demonstrate efficacy.13 The second “nonclassical
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