We investigated the involvement of extracellular signal-regulated protein k
inases (ERK) within spinal neurons in producing pain hypersensitivity. With
in a minute of an intense noxious peripheral or C-fiber electrical stimulus
, many phosphoERK-positive neurons were observed, most predominantly in lam
ina I and IIo of the ipsilateral dorsal horn. This staining was intensity a
nd NMDA receptor dependent. Low-intensity stimuli or A-fiber input had no e
ffect. Inhibition of ERK phosphorylation by a MEK inhibitor reduced the sec
ond phase of formalin-induced pain behavior, a measure of spinal neuron sen
sitization. ERK signaling within the spinal cord is therefore involved in g
enerating pain hypersensitivity. Because of its rapid activation, this effe
ct probably involves regulation of neuronal excitability without changes in
transcription.