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P2X4R+ microglia drive neuropathic pain

Abstract

Neuropathic pain, the most debilitating of all clinical pain syndromes, may be a consequence of trauma, infection or pathology from diseases that affect peripheral nerves. Here we provide a framework for understanding the spinal mechanisms of neuropathic pain as distinct from those of acute pain or inflammatory pain. Recent work suggests that a specific microglia response phenotype characterized by de novo expression of the purinergic receptor P2X4 is critical for the pathogenesis of pain hypersensitivity caused by injury to peripheral nerves. Stimulating P2X4 receptors initiates a core pain signaling pathway mediated by release of brain-derived neurotrophic factor, which produces a disinhibitory increase in intracellular chloride in nociceptive (pain-transmitting) neurons in the spinal dorsal horn. The changes caused by signaling from P2X4R+ microglia to nociceptive transmission neurons may account for the main symptoms of neuropathic pain in humans, and they point to specific interventions to alleviate this debilitating condition.

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Figure 1: Microglia; microdomains and proliferation after nerve injury.
Figure 2: The P2X4R+ microglial phenotype mediates a core pain hypersensitivity cascade following peripheral nerve injury.

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Acknowledgements

The work of the authors is supported by grants from the Canadian Institutes of Health Research (MT-11219), the Krembil Foundation and the Ontario Research Fund Research Excellence Program. M.W.S. is supported by a Canada Research Chair (Tier I) in Neuroplasticity and Pain, and the Anne and Max Tanenbaum Chair in Molecular Medicine at the Hospital for Sick Children. T.T. was supported by a Canadian Institutes of Health Research fellowship.

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Correspondence to Michael W Salter.

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Beggs, S., Trang, T. & Salter, M. P2X4R+ microglia drive neuropathic pain. Nat Neurosci 15, 1068–1073 (2012). https://doi.org/10.1038/nn.3155

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