Pain after nerve damage is an expression of pathological operation of the nervous
system, 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 P2X4 receptors (P2X4Rs), a subtype of ionotropic ATP receptor, reversed tactile
allodynia caused by peripheral nerve injury without affecting acute pain behaviours
in naive animals. After nerve injury, P2X4R expression increased strikingly in the
ipsilateral spinal cord, and P2X4Rs were induced in hyperactive microglia but not
in neurons or astrocytes. Intraspinal administration of P2X4R antisense oligodeoxynucleotide
decreased the induction of P2X4Rs and suppressed tactile allodynia after nerve injury.
Conversely, intraspinal administration of microglia in which P2X4Rs had been induced
and stimulated, produced tactile allodynia in naive rats. Taken together, our results
demonstrate that activation of P2X4Rs in hyperactive microglia is necessary for tactile
allodynia after nerve injury and is sufficient to produce tactile allodynia in normal
animals. Thus, blocking P2X4Rs in microglia might be a new therapeutic strategy for
pain induced by nerve injury.