Antihyperalgesic effect of joint mobilization requires Cav3.2 calcium channels

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Abstract

The present study was undertaken to explore the relative contributions of Cav3.2 T-type channels to mediating the antihyperalgesic activity of joint manipulation (JM) therapy. We used the chronic constriction injury model (CCI) to induce peripheral neuropathy and chronic pain in male mice, followed by JM. We demonstrate that JM produces long-lasting mechanical anti-hyperalgesia that is abolished in Cav3.2 null mice. Moreover, we found that JM displays a similar analgesic profile as the fatty acid amide hydrolase inhibitor URB597, suggesting a possible converging mechanism of action involving endocannabinoids. Overall, our findings advance our understanding of the mechanisms through which JM produces analgesia.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13041-023-01049-3.

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Most cited references 15

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Low-dose vaporized cannabis significantly improves neuropathic pain.

Barth Wilsey, Thomas Marcotte, Reena Deutsch … (2013)

We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain.

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Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide.

A Monteil, Francis E. Reyes, J Chemin … (2001)

Low-voltage-activated or T-type Ca(2+) channels (T-channels) are widely expressed, especially in the central nervous system where they contribute to pacemaker activities and are involved in the pathogenesis of epilepsy. Proper elucidation of their cellular functions has been hampered by the lack of selective pharmacology as well as the absence of generic endogenous regulations. We report here that both cloned (alpha(1G), alpha(1H) and alpha(1I) subunits) and native T-channels are blocked by the endogenous cannabinoid, anandamide. Anandamide, known to exert its physiological effects through cannabinoid receptors, inhibits T-currents independently from the activation of CB1/CB2 receptors, G-proteins, phospholipases and protein kinase pathways. Anandamide appears to be the first endogenous ligand acting directly on T-channels at submicromolar concentrations. Block of anandamide membrane transport by AM404 prevents T-current inhibition, suggesting that anandamide acts intracellularly. Anandamide preferentially binds and stabilizes T-channels in the inactivated state and is responsible for a significant decrease of T-currents associated with neuronal firing activities. Our data demonstrate that anandamide inhibition of T-channels can regulate neuronal excitability and account for CB receptor-independent effects of this signaling molecule.

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Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol.

Brian Ross, Mark Connor, I Napier (2008)

Delta(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prevalent biologically active constituents of Cannabis sativa. THC is the prototypic cannabinoid CB1 receptor agonist and is psychoactive and analgesic. CBD is also analgesic, but it is not a CB1 receptor agonist. Low voltage-activated T-type calcium channels, encoded by the Ca(V)3 gene family, regulate the excitability of many cells, including neurons involved in nociceptive processing. We examined the effects of THC and CBD on human Ca(V)3 channels stably expressed in human embryonic kidney 293 cells and T-type channels in mouse sensory neurons using whole-cell, patch clamp recordings. At moderately hyperpolarized potentials, THC and CBD inhibited peak Ca(V)3.1 and Ca(V)3.2 currents with IC(50) values of approximately 1 mum but were less potent on Ca(V)3.3 channels. THC and CBD inhibited sensory neuron T-type channels by about 45% at 1 mum. However, in recordings made from a holding potential of -70 mV, 100 nm THC or CBD inhibited more than 50% of the peak Ca(V)3.1 current. THC and CBD produced a significant hyperpolarizing shift in the steady state inactivation potentials for each of the Ca(V)3 channels, which accounts for inhibition of channel currents. Additionally, THC caused a modest hyperpolarizing shift in the activation of Ca(V)3.1 and Ca(V)3.2. THC but not CBD slowed Ca(V)3.1 and Ca(V)3.2 deactivation and inactivation kinetics. Thus, THC and CBD inhibit Ca(V)3 channels at pharmacologically relevant concentrations. However, THC, but not CBD, may also increase the amount of calcium entry following T-type channel activation by stabilizing open states of the channel.

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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): 18 July 2023

Publication date PMC-release: 18 July 2023

Publication date Collection: 2023

Volume: 16

Electronic Location Identifier: 60

Affiliations

[1 ]GRID grid.22072.35, ISNI 0000 0004 1936 7697, Departments of Clinical Neurosciences, and Physiology & Pharmacology, Hotchkiss Brain Institute, Alberta Children’s Hospital Research Institute, , University of Calgary, ; Calgary, AB T2N 4N1 Canada

[2 ]GRID grid.412287.a, ISNI 0000 0001 2150 7271, Experimental Neuroscience Laboratory (LaNEx), Postgraduate Program in Health Sciences, , University of Southern Santa Catarina, ; Palhoça, SC Brazil

[3 ]GRID grid.411237.2, ISNI 0000 0001 2188 7235, Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, , Universidade Federal de Santa Catarina, Campus Universitário-Trindade, ; Florianópolis, SC Brazil

[4 ]GRID grid.265892.2, ISNI 0000000106344187, Department of Physical Therapy, Rehabilitation Science Program, , University of Alabama at Birmingham, ; Birmingham, AL USA

Author information

Gerald W. Zamponi http://orcid.org/0000-0002-0644-9066

Article

Publisher ID: 1049

DOI: 10.1186/s13041-023-01049-3

PMC ID: 10355051

PubMed ID: 37464359

SO-VID: 1d0b736f-84df-4ef7-a6ce-7df975302cef

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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 : 11 June 2023

Date accepted : 12 July 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001804, Canada Research Chairs;

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Funded by: Alberta Innovates

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ScienceOpen disciplines: Neurosciences

Keywords: joint mobilization therapy,cav3.2 channel,mechanical hyperalgesia,analgesia

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ScienceOpen disciplines: Neurosciences

Keywords: joint mobilization therapy, cav3.2 channel, mechanical hyperalgesia, analgesia

Antihyperalgesic effect of joint mobilization requires Cav3.2 calcium channels

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Most cited references 15

Low-dose vaporized cannabis significantly improves neuropathic pain.

Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide.

Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol.

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