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      Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain

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          Abstract

          Low dose of cannabidiol ameliorates mechanical allodynia and anxious behavior and restores impaired serotonergic transmission in a neuropathic pain model in rats.

          Abstract

          Clinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis that interacts with the serotonin (5-HT) 1A receptor, may possess analgesic and anxiolytic effects. However, its effects on 5-HT neuronal activity, as well as its impact on models of neuropathic pain are unknown. First, using in vivo single-unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus, which was prevented by administration of the 5-HT 1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV 1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB 1 receptor antagonist AM 251 (1 mg/kg, i.v.). Repeated treatment with CBD (5 mg/kg/day, subcutaneously [s.c.], for 7 days) increased 5-HT firing through desensitization of 5-HT 1A receptors. Rats subjected to the spared nerve injury model for 24 days showed decreased 5-HT firing activity, mechanical allodynia, and increased anxiety-like behavior in the elevated plus maze test, open-field test, and novelty-suppressed feeding test. Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Antiallodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), whereas the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV 1 activation, reduces anxiety through 5-HT 1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.

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          Most cited references74

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          Spared nerve injury: an animal model of persistent peripheral neuropathic pain.

          Peripheral neuropathic pain is produced by multiple etiological factors that initiate a number of diverse mechanisms operating at different sites and at different times and expressed both within, and across different disease states. Unraveling the mechanisms involved requires laboratory animal models that replicate as far as possible, the different pathophysiological changes present in patients. It is unlikely that a single animal model will include the full range of neuropathic pain mechanisms. A feature of several animal models of peripheral neuropathic pain is partial denervation. In the most frequently used models a mixture of intact and injured fibers is created by loose ligation of either the whole (Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107) or a tight ligation of a part (Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990;43:205-218) of a large peripheral nerve, or a tight ligation of an entire spinal segmental nerve (Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992;50:355-363). We have developed a variant of partial denervation, the spared nerve injury model. This involves a lesion of two of the three terminal branches of the sciatic nerve (tibial and common peroneal nerves) leaving the remaining sural nerve intact. The spared nerve injury model differs from the Chung spinal segmental nerve, the Bennett chronic constriction injury and the Seltzer partial sciatic nerve injury models in that the co-mingling of distal intact axons with degenerating axons is restricted, and it permits behavioral testing of the non-injured skin territories adjacent to the denervated areas. The spared nerve injury model results in early ( 6 months), robust (all animals are responders) behavioral modifications. The mechanical (von Frey and pinprick) sensitivity and thermal (hot and cold) responsiveness is increased in the ipsilateral sural and to a lesser extent saphenous territories, without any change in heat thermal thresholds. Crush injury of the tibial and common peroneal nerves produce similar early changes, which return, however to baseline at 7-9 weeks. The spared nerve injury model may provide, therefore, an additional resource for unraveling the mechanisms responsible for the production of neuropathic pain.
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            Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.

            Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.
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              Agonistic properties of cannabidiol at 5-HT1a receptors.

              Cannabidiol (CBD) is a major, biologically active, but psycho-inactive component of cannabis. In this cell culture-based report, CBD is shown to displace the agonist, [3H]8-OH-DPAT from the cloned human 5-HT1a receptor in a concentration-dependent manner. In contrast, the major psychoactive component of cannabis, tetrahydrocannabinol (THC) does not displace agonist from the receptor in the same micromolar concentration range. In signal transduction studies, CBD acts as an agonist at the human 5-HT1a receptor as demonstrated in two related approaches. First, CBD increases [35S]GTPgammaS binding in this G protein coupled receptor system, as does the known agonist serotonin. Second, in this GPCR system, that is negatively coupled to cAMP production, both CBD and 5-HT decrease cAMP concentration at similar apparent levels of receptor occupancy, based upon displacement data. Preliminary comparative data is also presented from the cloned rat 5-HT2a receptor suggesting that CBD is active, but less so, relative to the human 5-HT1a receptor, in binding analyses. Overall, these studies demonstrate that CBD is a modest affinity agonist at the human 5-HT1a receptor. Additional work is required to compare CBD's potential at other serotonin receptors and in other species. Finally, the results indicate that cannabidiol may have interesting and useful potential beyond the realm of cannabinoid receptors.
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                Author and article information

                Journal
                Pain
                Pain
                JPAIN
                Pain
                JOP
                Pain
                Wolters Kluwer (Philadelphia, PA )
                0304-3959
                1872-6623
                January 2019
                28 December 2018
                : 160
                : 1
                : 136-150
                Affiliations
                [a ]Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada
                [b ]Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA, United States
                [c ]Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada
                [d ]Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania “Luigi Vanvitelli,” Naples, Italy
                [e ]Division of Neuroscience, San Raffaele Scientific Institute and Vita Salute University, Milan, Italy
                Author notes
                [* ]Corresponding author. Address: Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Room 220, Irving Ludmer Psychiatry Research and Training Building, 1033 Pine Ave West, McGill University, Montreal, PQ H3A 1A1, Canada. Tel.: +1-514-398-1290; fax: +1-514-398-4866. E-mail address: gabriella.gobbi@ 123456mcgill.ca (G. Gobbi).
                Article
                PAIN-D-18-00287 00016
                10.1097/j.pain.0000000000001386
                6319597
                30157131
                8079d77e-2d55-40f8-b86e-1ce4bf848fda
                Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                : 19 March 2018
                : 02 August 2018
                Categories
                Research Paper
                Custom metadata
                TRUE

                Anesthesiology & Pain management
                cannabidiol,pain,dorsal raphe,electrophysiology,anxiety
                Anesthesiology & Pain management
                cannabidiol, pain, dorsal raphe, electrophysiology, anxiety

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