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 (paintransmitting) 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.

P2X ion channel receptors and inflammation

“…Data has been presented to indicate that antagonism of spinal P2X3/P2X2/3 receptors regulates an indirect activation of the opioid system to alleviate inflammatory hyperalgesia [105]. P2X4 receptors probably also participate because of their involvement in neuropathic pain [106,107], which is relevant for inflammation. Mice lacking P2X4 receptors show impaired inflammasome activation [40] and do not develop pain hypersensitivity in response to inflammatory agents, and this is paralleled by a complete absence of PGE 2 in inflammatory exudates [30].…”

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

“…Spinal cord microglia quickly react to injury (including peripheral nerve damage), by first acquiring a phagocytic phenotype and then releasing large amounts of inflammatory mediators [63]. This pro-inflammatory extracellular milieu can dramatically influence synaptic activity and neuronal firing of second-order neurons in the spinal cord dorsal horn, and ultimately contribute to the generation and maintenance of chronic neuropathic pain [63].…”

“…This pro-inflammatory extracellular milieu can dramatically influence synaptic activity and neuronal firing of second-order neurons in the spinal cord dorsal horn, and ultimately contribute to the generation and maintenance of chronic neuropathic pain [63].…”

Mechanism for Increased Expression of UGT2B in the Liver of Mice with Neuropathic Pain

“…It has also been reported that expression of the ligand-gated ion channel pregnane 2 recepter (P2X) receptor is increased in activated microglia. 8,[10][11][12] This induces the release of brain-derived neurotrophic factor (BDNF) from microglia, which binds to the tyrosine kinase receptor B (TrkB) receptor on secondary sensory nerves, downregulating the expression of K-Cl cotransporter 2 (KCC2). 13,14) The reduced expression of KCC2 disinhibits GABAergic neurons, which suppress the sensation of pain under normal conditions, resulting in pain enhancement.…”