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Nonpsychotropic Plant Cannabinoids, Cannabidivarin (CBDV) and Cannabidiol (CBD), Activate and Desensitize Transient Receptor Potential Vanilloid 1 (TRPV1) Channels in Vitro: Potential for the Treatment of Neuronal Hyperexcitability

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    Research Article

    Nonpsychotropic Plant Cannabinoids, Cannabidivarin (CBDV) and Cannabidiol (CBD), Activate and Desensitize Transient Receptor Potential Vanilloid 1 (TRPV1) Channels in Vitro: Potential for the Treatment of Neuronal Hyperexcitability
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    † Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Council of Research (CNR), 80078 Pozzuoli (NA) Italy
    ‡ School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AJ, United Kingdom
    ∥ Science of Health Department, §School of Pharmacy and ∥School of Medicine, University of Catanzaro, 88100 Catanzaro, Italy
    *Mailing address: Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Council of Research (CNR), Via Campi Flegrei 34, Comprensorio Olivetti, 80078, Pozzuoli (NA) Italy. Tel: +39-081-8675093. Fax: +39-081-8041770. E-mail: [email protected]
    *Mailing address: School of Pharmacy, University of Reading, Whiteknights, PO Box 228, Reading RG6 6AJ, UK. Tel: +44 118 378 6156. Fax: +44-118-3786542. E-mail: [email protected]
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    ACS Chemical Neuroscience

    Cite this: ACS Chem. Neurosci. 2014, 5, 11, 1131–1141
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    https://doi.org/10.1021/cn5000524
    Published July 16, 2014
    Copyright © 2014 American Chemical Society
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    Abstract

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    Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg2+-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg2+-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg2+-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy.

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    Supplementary Figure 1: Effects of CBDV and CBD in HEK293 cells transiently expressing rat TRPV2 channels. Supplementary Figure 2: Representative MEA traces taken from single electrodes located in the CA1 region of hippocampal slices in control and when exposed to the TRPV1 agonist capsaicin (CAPS; 10 μM), CBDV (10 μM), CBDV in the presence of IRTX (10 μM and 1 μM, respectively), and CAPS plus IRTX (10 μM and 1 μM, respectively). Supplementary Table 1: Sequence of primers used for qPCR analysis This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: ACS Chem. Neurosci. 2014, 5, 11, 1131–1141
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