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      Analgesia by intrathecal delta-9-tetrahydrocannabinol is dependent on Cav3.2 calcium channels

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          Abstract

          Delta-9-tetrahydrocannabinol (Δ 9-THC) is known to produce systemic analgesia that involves CB 1 and CB 2 cannabinoid receptors. However, there is compelling evidence that Δ 9-THC can potently inhibit Cav3.2T-type calcium channels which are highly expressed in dorsal root ganglion neurons and in the dorsal horn of the spinal cord. Here, we investigated whether spinal analgesia produced by Δ 9-THC involves Cav3.2 channels vis a vis cannabinoid receptors. We show that spinally delivered Δ 9-THC produced dose-dependent and long-lasting mechanical anti-hyperalgesia in neuropathic mice, and showed potent analgesic effects in models of inflammatory pain induced by formalin or Complete Freund’s Adjuvant (CFA) injection into the hind paw, with the latter showing no overt sex differences. The Δ 9-THC mediated reversal of thermal hyperalgesia in the CFA model was abolished in Cav3.2 null mice, but was unaltered in CB 1 and CB 2 null animals. Hence, the analgesic effects of spinally delivered Δ 9-THC are due to an action on T-type calcium channels, rather than activation of spinal cannabinoid receptors.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13041-023-01036-8.

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          The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.

          R Pertwee (2008)
          Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Delta9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Delta9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.
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            Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception.

            John McRory, Brigitte Couette, Olivier Poirot … (2005)
            Analgesic therapies are still limited and sometimes poorly effective, therefore finding new targets for the development of innovative drugs is urgently needed. In order to validate the potential utility of blocking T-type calcium channels to reduce nociception, we explored the effects of intrathecally administered oligodeoxynucleotide antisenses, specific to the recently identified T-type calcium channel family (CaV3.1, CaV3.2, and CaV3.3), on reactions to noxious stimuli in healthy and mononeuropathic rats. Our results demonstrate that the antisense targeting CaV3.2 induced a knockdown of the CaV3.2 mRNA and protein expression as well as a large reduction of 'CaV3.2-like' T-type currents in nociceptive dorsal root ganglion neurons. Concomitantly, the antisense treatment resulted in major antinociceptive, anti-hyperalgesic, and anti-allodynic effects, suggesting that CaV3.2 plays a major pronociceptive role in acute and chronic pain states. Taken together, the results provide direct evidence linking CaV3.2 T-type channels to pain perception and suggest that CaV3.2 may offer a specific molecular target for the treatment of pain.
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              The deubiquitinating enzyme USP5 modulates neuropathic and inflammatory pain by enhancing Cav3.2 channel activity.

              Gerald Zamponi, Amaury Francois, Anne Pizzoccaro … (2014)
              T-type calcium channels are essential contributors to the transmission of nociceptive signals in the primary afferent pain pathway. Here, we show that T-type calcium channels are ubiquitinated by WWP1, a plasma-membrane-associated ubiquitin ligase that binds to the intracellular domain III-IV linker region of the Cav3.2 T-type channel and modifies specific lysine residues in this region. A proteomic screen identified the deubiquitinating enzyme USP5 as a Cav3.2 III-IV linker interacting partner. Knockdown of USP5 via shRNA increases Cav3.2 ubiquitination, decreases Cav3.2 protein levels, and reduces Cav3.2 whole-cell currents. In vivo knockdown of USP5 or uncoupling USP5 from native Cav3.2 channels via intrathecal delivery of Tat peptides mediates analgesia in both inflammatory and neuropathic mouse models of mechanical hypersensitivity. Altogether, our experiments reveal a cell signaling pathway that regulates T-type channel activity and their role in nociceptive signaling. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Gerald W. Zamponi:
                ORCID: http://orcid.org/0000-0002-0644-9066
                zamponi@ucalgary.ca
                Journal
                Journal ID (nlm-ta): Mol Brain
                Journal ID (iso-abbrev): Mol Brain
                Title: Molecular Brain
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1756-6606
                Publication date (Electronic): 25 May 2023
                Publication date PMC-release: 25 May 2023
                Publication date Collection: 2023
                Volume: 16
                Electronic Location Identifier: 47
                Affiliations
                [1 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Department of Clinical Neurosciences, , University of Calgary, ; Calgary, AB Canada
                [2 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Alberta Children’s Hospital Research Institute, , University of Calgary, ; Calgary, AB Canada
                [3 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Hotchkiss Brain Institute, , University of Calgary, ; Calgary, AB Canada
                [4 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Cumming School of Medicine, , University of Calgary, ; Calgary, AB Canada
                Author information
                http://orcid.org/0000-0002-0644-9066
                Article
                Publisher ID: 1036
                DOI: 10.1186/s13041-023-01036-8
                PMC ID: 10210369
                PubMed ID: 37231418
                SO-VID: da35c1d9-cbd5-4d49-8447-c4a7a23fd628
                Copyright © © The Author(s) 2023
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 26 April 2023
                Date accepted : 17 May 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001804, Canada Research Chairs;
                Funded by: Alberta Innovates
                Categories
                Subject: Micro Report
                Custom metadata
                issue-copyright-statement © Min Zhuo, Bong-Kiun Kaang and BioMed central Ltd. 2023

                ScienceOpen disciplines: Neurosciences
                Keywords: δ9-thc,cannabinoid receptors,cav3.2 channel,analgesia,pain
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: δ9-thc, cannabinoid receptors, cav3.2 channel, analgesia, pain

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