P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury

Pain after nerve damage is an expression of pathological operation of the nervous system 1,2, one hallmark of which is tactile allodynia-pain hypersensitivity evoked by innocuous stimuli. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. Here we report that pharmacological blockade of spinal P2X(4) receptors (P2X(4)Rs)(3-7), a subtype of ionotropic ATP receptor(8), reversed tactile allodynia caused by peripheral nerve injury without affecting acute pain behaviours in naive animals. After nerve injury, P2X(4)R expression increased strikingly in the ipsilateral spinal cord, and P2X(4)Rs were induced in hyperactive microglia but not in neurons or astrocytes. Intraspinal administration of P2X(4)R antisense oligodeoxynucleotide decreased the induction of P2X(4)Rs and suppressed tactile allodynia after nerve injury. Conversely, intraspinal administration of microglia in which P2X(4)Rs had been induced and stimulated, produced tactile allodynia in naive rats. Taken together, our results demonstrate that activation of P2X(4)Rs in hyperactive microglia is necessary for tactile allodynia after nerve injury and is sufficient to produce tactile allodynia in normal animals. Thus, blocking P2X(4)Rs in microglia might be a new therapeutic strategy for pain induced by nerve injury.