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      Cannabinoids and Reproduction: A Lasting and Intriguing History

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          Abstract

          Starting from an historical overview of lasting Cannabis use over the centuries, we will focus on a description of the cannabinergic system, with a comprehensive analysis of chemical and pharmacological properties of endogenous and synthetic cannabimimetic analogues. The metabolic pathways and the signal transduction mechanisms, activated by cannabinoid receptors stimulation, will also be discussed. In particular, we will point out the action of cannabinoids and endocannabinoids on the different neuronal networks involved in reproductive axis, and locally, on male and female reproductive tracts, by emphasizing the pivotal role played by this system in the control of fertility.

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          Molecular characterization of a peripheral receptor for cannabinoids.

          S. MUNRO, K L Thomas, M. Abu-Shaar … (1993)
          The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
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            Structure of a cannabinoid receptor and functional expression of the cloned cDNA.

            L Matsuda, S Lolait, M J Brownstein … (1990)
            Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
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              The orphan receptor GPR55 is a novel cannabinoid receptor.

              E Ryberg, N. Larsson, S Sjögren … (2007)
              The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes. Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgammaS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways. We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgammaS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1 or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Galpha13 and can mediate activation of rhoA, cdc42 and rac1. These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiological function(s).
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                Author and article information

                Journal
                Journal ID (nlm-ta): Pharmaceuticals (Basel)
                Journal ID (iso-abbrev): Pharmaceuticals (Basel)
                Journal ID (publisher-id): pharmaceuticals
                Title: Pharmaceuticals
                Publisher: MDPI
                ISSN (Electronic): 1424-8247
                Publication date (Electronic): 25 October 2010
                Publication date Collection: October 2010
                Volume: 3
                Issue: 10
                Pages: 3275-3323
                Affiliations
                [1 ]Dipartimento di Medicina Sperimentale, Sez. “F. Bottazzi”, Seconda Università degli Studi di Napoli, Napoli, Italy
                [2 ]Dipartimento di Studi delle Istituzioni e dei Sistemi Territoriali, Università di Napoli “Parthenope”, Napoli, Italy
                Author notes
                [†]

                These authors contributed equally to the paper.

                [#]

                Equally senior authors.

                [* ]Author to whom correspondence should be addressed; E-Mail: riccardo.pierantoni@ 123456unina2.it .
                Article
                Publisher ID: pharmaceuticals-03-03275
                DOI: 10.3390/ph3103275
                PMC ID: 4034092
                SO-VID: 92fae36d-b39f-4a59-9443-269689e2e4b3
                Copyright © © 2010 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an Open Access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 12 August 2010
                Date revision received : 09 September 2010
                Date accepted : 21 October 2010
                Categories
                Subject: Review

                Keywords: cannabinergic system,male reproduction,female reproduction,hypothalamus-pituitary-gonads axis
                Data availability:
                Keywords: cannabinergic system, male reproduction, female reproduction, hypothalamus-pituitary-gonads axis

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