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Targeting P2X receptor signaling for chronic visceral pain and beyond

Biyu Shen1, Hong-Hong Zhang2, Cailin Wang3

  • 1Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, 215123, PR China; Shanghai Children's Medical Center affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Member of the Pain Translational Research Committee of the Shanghai Society for Neuroscience, Shanghai, PR China.

Neuropharmacology
|June 5, 2026
PubMed

Insights

Chronic visceral pain (CVP) involves ATP-P2X3/4/7 receptors and epigenetic changes. A precision medicine approach using epigenome editing and novel biomarkers may offer new CVP treatments.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • P2X receptors (P2XRs) are critical ATP-gated ion channels involved in chronic visceral pain (CVP).
  • The ATP-P2X3/4/7 axis drives peripheral and central sensitization in CVP.
  • Epigenetic modifications, like DNA methylation, contribute to persistent pain and limit antagonist efficacy.

Purpose of the Study:

  • To review the role of the ATP-P2X3/4/7 axis in CVP.
  • To highlight novel epigenetic mechanisms, including miR-1306-3p and P2RX7 methylation, in CVP.
  • To propose a precision medicine framework for overcoming challenges in CVP treatment.

Main Methods:

  • Review of current literature on P2XRs and CVP.
  • Analysis of epigenetic mechanisms (non-coding RNA, DNA methylation) in pain pathways.
  • Proposal of a precision medicine strategy incorporating epigenome editing, ATP biomarkers, and iPSC-derived neuron screening.

Main Results:

  • miR-1306-3p acts as an endogenous agonist for P2X3 receptors, linking stress to visceral pain.
  • Persistent DNA methylation at the P2RX7 locus in spinal astrocytes creates a 'pain memory'.
  • First-generation P2X3/P2X7 antagonists failed due to pharmacological issues and epigenetic resistance.

Conclusions:

  • A precision medicine framework integrating epigenome editing (CRISPR-dCas9), sweat-ATP biomarkers, and iPSC screening is proposed.
  • This approach aims to address limitations of current CVP treatments, including irreversible central sensitization.
  • The proposed framework holds potential for treating CVP associated with IBS and other pain conditions.
Keywords:
Chronic visceral painEpigeneticsP2X receptorsPrecision medicineSensitization

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