Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice

Damien Gilabert; Alexia Duveau; Sara Carracedo; Nathalie Linck; Adeline Langla; Rieko Muramatsu; Friedrich Koch-Nolte; François Rassendren; Thomas Grutter; Pascal Fossat; Eric Boué-Grabot; Lauriane Ulmann

doi:10.1016/j.isci.2023.108110

Microglial P2X4 receptors are essential for spinal neurons hyperexcitability and tactile allodynia in male and female neuropathic mice

iScience. 2023 Oct 2;26(11):108110. doi: 10.1016/j.isci.2023.108110. eCollection 2023 Nov 17.

Authors

Damien Gilabert^{1

2}, Alexia Duveau³, Sara Carracedo³, Nathalie Linck^{1

2}, Adeline Langla³, Rieko Muramatsu⁴, Friedrich Koch-Nolte⁵, François Rassendren^{1

2}, Thomas Grutter⁶, Pascal Fossat³, Eric Boué-Grabot³, Lauriane Ulmann^{1

2}

Affiliations

¹ IGF, University Montpellier, CNRS, INSERM, F-34094 Montpellier, France.
² LabEx Ion Channel Science and Therapeutics, Montpellier, France.
³ University Bordeaux, CNRS, IMN, UMR 5293, F-33000 Bordeaux, France.
⁴ Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
⁵ Institute of Immunology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
⁶ University of Strasbourg, CNRS, CAMB UMR 7199, F-67000 Strasbourg, France.

Abstract

In neuropathic pain, recent evidence has highlighted a sex-dependent role of the P2X4 receptor in spinal microglia in the development of tactile allodynia following nerve injury. Here, using internalization-defective P2X4mCherryIN knockin mice (P2X4KI), we demonstrate that increased cell surface expression of P2X4 induces hypersensitivity to mechanical stimulations and hyperexcitability in spinal cord neurons of both male and female naive mice. During neuropathy, both wild-type (WT) and P2X4KI mice of both sexes develop tactile allodynia accompanied by spinal neuron hyperexcitability. These responses are selectively associated with P2X4, as they are absent in global P2X4KO or myeloid-specific P2X4KO mice. We show that P2X4 is de novo expressed in reactive microglia in neuropathic WT and P2X4KI mice of both sexes and that tactile allodynia is relieved by pharmacological blockade of P2X4 or TrkB. These results show that the upregulation of P2X4 in microglia is crucial for neuropathic pain, regardless of sex.

Keywords: Behavioral neuroscience; Biological sciences; Natural sciences; Neuroscience; Pathophysiology; Physiology; Sensory neuroscience.