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Abstract & Commentary
Source: Tsuda M, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature. 2003;424:778-783.
Neuropathic pain, specifically allodynia following peripheral nerve injury, is a poorly understood phenomenon that challenges clinicians and patients. Tsuda and associates report on animal data that may reveal insights into the underlying mechanism of tactile allodynia. They examined behavioral, structural, and functional changes in the rat dorsal horn in response to a peripheral nerve (L5) injury. Six significant observations appeared: 1) Ipsilateral to the lesion, "hyperactive" microglia cells increased in number and demonstrated a 5.4-fold increase in expression of P2X4 receptors; 2) P2X4 receptor-specific antagonists reversed allodynia, whereas broad P2X receptor antagonists (but without P2X4 activity) did not reverse the allodynia; 3) Fluorescent antibody labeling proved the localization of P2X4 on microglia; 4) Western blot analysis showed that increased expression of P2X4 receptors directly correlated with allodynia and reached a maximum at day 14; 5) Blocked expression of P2X4 receptor by intrathecal antisense oligodeoxynucleotide blocked the development of allodynia; and 6) Activated microglial cells injected into naïve rats induced allodynia. Tsuda et al speculate that via the P2X4R receptor, "activated" microglia might release cytokines that enhance synaptic transmission in spinal pain pathways.
The P2X4 is a purine-type ion channel receptor with 7 subtypes and wide expression throughout the nervous system. It binds to ATP and regulates the influx of Na+ and Ca++. This work is important on several levels. First, it demonstrates in a way heretofore not fully appreciated the dynamic inter-relationship between glia and neurons in pain. A multistep process emerges of nerve injury, inducing glia activation, resulting in neuronal hypersensitivity. One can speculate that other pathophysiological mechanisms, such as degenerative brain disease, may result from a similar interaction. This work opens the door for drug targets that can either inhibit P2X4 receptor and/or prevent upregulation of P2X4 receptor expression. — Jeffrey Reich, MD, Assistant Professor of Neurology, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.