Microglia-neuronal communication mediated by P2X4R-BDNF-TrkB promotes synaptic plasticity and anterior cingulate cortex hyperactivity in muscle pain chronicity.

British journal of anaesthesia 2025

Liang Y, Luo M, Xu Q, Zhang S, Niu S, Li X, Sun W, Song M, Wang L, Xing X, Wang J, Feng M, Zhao L, Chen H, Sheng R, Wang Y

Abstract

BACKGROUND: Microglia-neuronal communication is crucial for the development and maintenance of pain. However, the exact mechanisms underlying this interaction and its role in anterior cingulate cortex (ACC) circuitry in pain regulation are under exploration. METHODS: We explored the role of P2X4R-brain-derived neurotrophic factor (BDNF)-TrkB signalling of ACC in regulating muscle pain (MP). Mechanical and thermal pain thresholds along with open field tests were used to assess pain and anxiety-like behaviours. Golgi staining, transmission electron microscopy, and patch-clamp recordings were performed to evaluate synaptic plasticity changes. Meanwhile, cFos staining and calcium imaging substantiate the neuronal excitability. In addition, we used chemogenetic and optogenetic approaches to manipulate ACC neuronal activity. RESULTS: The ACC exhibited increased excitability, together with enhanced synaptic plasticity in rats with chronic MP. Microglial inhibition alleviated pain and anxiety-like behaviours. Furthermore, microglial P2X4R promoted BDNF expression, which acted on TrkB to regulate neuronal excitability and synaptic plasticity in ACC; these effects were reversed by P2X4R knockdown and TrkB inhibition in MP. Chemogenetic and optogenetic suppression of ACC hyperactivity relieved chronic MP and anxiety-like behaviours. CONCLUSIONS: Our findings highlight a critical microglia-neuronal communication via the P2X4R-BDNF-TrkB signalling, which enhances synaptic plasticity and cortical excitability in the anterior cingulate cortex, thereby participating in the regulation of muscle pain. Understanding how to assess and modulate microglia-neuronal communication and abnormal cortical activity will be key to developing novel therapies for MP disorders.

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