Intrathecal delivery of a palmitoylated peptide targeting Y382-384 within the P2X7 receptor alleviates neuropathic pain

Molecular Pain
Rebecca DalgarnoTuan Trang

Abstract

Pain hypersensitivity resulting from peripheral nerve injury depends on pathological microglial activation in the dorsal horn of the spinal cord. This microglial activity is critically modulated by P2X7 receptors (P2X7R) and ATP stimulation of these receptors produces mechanical allodynia, a defining feature of neuropathic pain. Peripheral nerve injury increases P2X7R expression and potentiates its cation channel function in spinal microglia. Here, we report a means to preferentially block the potentiation of P2X7R function by delivering a membrane permeant small interfering peptide that targets Y382-384, a putative tyrosine phosphorylation site within the P2X7R intracellular C-terminal domain. Intrathecal administration of this palmitoylated peptide (P2X7R379-389) transiently reversed mechanical allodynia caused by peripheral nerve injury in both male and female rats. Furthermore, targeting Y382-384 suppressed P2X7R-mediated release of cytokine tumor necrosis factor alpha and blocked the adoptive transfer of mechanical allodynia caused by intrathecal injection of P2X7R-stimulated microglia. Thus, Y382-384 site-specific modulation of P2X7R is an important microglial mechanism in neuropathic pain.

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Citations

Mar 19, 2020·Pain·Kenneth A JacobsonDaniela Salvemini
Aug 23, 2019·Expert Review of Clinical Pharmacology·Timothy R DeerJason Pope
Nov 30, 2019·Brain Research Bulletin·Wen-Jun ZhangZeng-Xu Liu
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Jul 14, 2021·Pain·Ann M GregusMatthew W Buczynski
Nov 21, 2021·Purinergic Signalling·Wen-Jing Ren, Peter Illes

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Methods Mentioned

BETA
flow cytometry
dissection
Protein Assay
ELISA
Fluorescence

Software Mentioned

GraphPad Prism
ImageJ
EasyRatioPro
E2
C1

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