Centrally expressed Cav3.2 T-type calcium channel is critical for the initiation and maintenance of neuropathic pain

  1. Sophie L Fayad
  2. Guillaume Ourties
  3. Benjamin Le Gac
  4. Baptiste Jouffre
  5. Sylvain Lamoine
  6. Antoine Fruquière
  7. Sophie Laffray
  8. Laila Gasmi
  9. Bruno Cauli
  10. Christophe Mallet
  11. Emmanuel Bourinet
  12. Thomas Bessaih
  13. Régis C Lambert  Is a corresponding author
  14. Nathalie Leresche
  1. Sorbonne University, CNRS, INSERM, France
  2. Université Clermont Auvergne, Inserm, France
  3. Université de Montpellier, CNRS, INSERM, France

Abstract

Cav3.2 T-type calcium channel is a major molecular actor of neuropathic pain in peripheral sensory neurons, but its involvement at the supra-spinal level is almost unknown. In the Anterior Pretectum (APT), a hub of connectivity of the somatosensory system involved in pain perception, we show that Cav3.2 channels are expressed in a sub-population of GABAergic neurons co-expressing parvalbumin (PV). In these PV-expressing neurons, Cav3.2 channels contribute to a high frequency bursting activity, which is increased in the spared nerve injury model of neuropathy. Specific deletion of Cav3.2 channels in APT neurons reduced both the initiation and maintenance of mechanical and cold allodynia. These data are a direct demonstration that centrally expressed Cav3.2 channels also play a fundamental role in pain pathophysiology.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Sophie L Fayad

    Sorbonne University, CNRS, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4834-6524
  2. Guillaume Ourties

    Université Clermont Auvergne, Inserm, Clermont-Ferrand, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Benjamin Le Gac

    Sorbonne University, CNRS, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Baptiste Jouffre

    Université Clermont Auvergne, Inserm, Clermont-Ferrand, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Sylvain Lamoine

    Université Clermont Auvergne, Inserm, Clermont-Ferrand, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Antoine Fruquière

    Université de Montpellier, CNRS, INSERM, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Sophie Laffray

    Université de Montpellier, CNRS, INSERM, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Laila Gasmi

    Sorbonne University, CNRS, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Bruno Cauli

    Sorbonne University, CNRS, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1471-4621
  10. Christophe Mallet

    Université Clermont Auvergne, Inserm, Clermont-Ferrand, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0873-6763
  11. Emmanuel Bourinet

    Université de Montpellier, CNRS, INSERM, Montpellier, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Thomas Bessaih

    Sorbonne University, CNRS, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0764-7731
  13. Régis C Lambert

    Sorbonne University, CNRS, INSERM, Paris, France
    For correspondence
    regis.lambert@sorbonne-universite.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8972-1151
  14. Nathalie Leresche

    Sorbonne University, CNRS, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6705-9769

Funding

Agence Nationale de la Recherche (ANR-15-CE16-0012-03)

  • Emmanuel Bourinet

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures complied with the ethical guidelines of the Federation for Laboratory Animal Science Associations (FELASA) and with the approval of the French National Consultative Ethics Committee for health and life sciences (authorization number: 17958).

Reviewing Editor

  1. Gary L Westbrook, Oregon Health & Science University, United States

Version history

  1. Received: March 28, 2022
  2. Preprint posted: April 29, 2022 (view preprint)
  3. Accepted: November 22, 2022
  4. Accepted Manuscript published: November 23, 2022 (version 1)
  5. Version of Record published: December 1, 2022 (version 2)

Copyright

© 2022, Fayad et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 833
    Page views
  • 159
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Sophie L Fayad
  2. Guillaume Ourties
  3. Benjamin Le Gac
  4. Baptiste Jouffre
  5. Sylvain Lamoine
  6. Antoine Fruquière
  7. Sophie Laffray
  8. Laila Gasmi
  9. Bruno Cauli
  10. Christophe Mallet
  11. Emmanuel Bourinet
  12. Thomas Bessaih
  13. Régis C Lambert
  14. Nathalie Leresche
(2022)
Centrally expressed Cav3.2 T-type calcium channel is critical for the initiation and maintenance of neuropathic pain
eLife 11:e79018.
https://doi.org/10.7554/eLife.79018

Further reading

    1. Neuroscience
    Weiwei Qui, Chelsea R Hutch ... Darleen Sandoval
    Research Article

    Several discrete groups of feeding-regulated neurons in the nucleus of the solitary tract (nucleus tractus solitarius; NTS) suppress food intake, including avoidance-promoting neurons that express Cck (NTSCck cells) and distinct Lepr- and Calcr-expressing neurons (NTSLepr and NTSCalcr cells, respectively) that suppress food intake without promoting avoidance. To test potential synergies among these cell groups we manipulated multiple NTS cell populations simultaneously. We found that activating multiple sets of NTS neurons (e.g., NTSLepr plus NTSCalcr (NTSLC), or NTSLC plus NTSCck (NTSLCK)) suppressed feeding more robustly than activating single populations. While activating groups of cells that include NTSCck neurons promoted conditioned taste avoidance (CTA), NTSLC activation produced no CTA despite abrogating feeding. Thus, the ability to promote CTA formation represents a dominant effect but activating multiple non-aversive populations augments the suppression of food intake without provoking avoidance. Furthermore, silencing multiple NTS neuron groups augmented food intake and body weight to a greater extent than silencing single populations, consistent with the notion that each of these NTS neuron populations plays crucial and cumulative roles in the control of energy balance. We found that silencing NTSLCK neurons failed to blunt the weight-loss response to vertical sleeve gastrectomy (VSG) and that feeding activated many non-NTSLCK neurons, however, suggesting that as-yet undefined NTS cell types must make additional contributions to the restraint of feeding.

    1. Genetics and Genomics
    2. Neuroscience
    Ji-Eun Ahn, Hubert Amrein
    Research Article

    In the fruit fly Drosophila melanogaster, gustatory sensory neurons express taste receptors that are tuned to distinct groups of chemicals, thereby activating neural ensembles that elicit either feeding or avoidance behavior. Members of a family of ligand -gated receptor channels, the Gustatory receptors (Grs), play a central role in these behaviors. In general, closely related, evolutionarily conserved Gr proteins are co-expressed in the same type of taste neurons, tuned to chemically related compounds, and therefore triggering the same behavioral response. Here, we report that members of the Gr28 subfamily are expressed in largely non-overlapping sets of taste neurons in Drosophila larvae, detect chemicals of different valence, and trigger opposing feeding behaviors. We determined the intrinsic properties of Gr28 neurons by expressing the mammalian Vanilloid Receptor 1 (VR1), which is activated by capsaicin, a chemical to which wild-type Drosophila larvae do not respond. When VR1 is expressed in Gr28a neurons, larvae become attracted to capsaicin, consistent with reports showing that Gr28a itself encodes a receptor for nutritious RNA. In contrast, expression of VR1 in two pairs of Gr28b.c neurons triggers avoidance to capsaicin. Moreover, neuronal inactivation experiments show that the Gr28b.c neurons are necessary for avoidance of several bitter compounds. Lastly, behavioral experiments of Gr28 deficient larvae and live Ca2+ imaging studies of Gr28b.c neurons revealed that denatonium benzoate, a synthetic bitter compound that shares structural similarities with natural bitter chemicals, is a ligand for a receptor complex containing a Gr28b.c or Gr28b.a subunit. Thus, the Gr28 proteins, which have been evolutionarily conserved over 260 million years in insects, represent the first taste receptor subfamily in which specific members mediate behavior with opposite valence.