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Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity

Abstract

We investigated the involvement of extracellular signal-regulated protein kinases (ERK) within spinal neurons in producing pain hypersensitivity. Within a minute of an intense noxious peripheral or C-fiber electrical stimulus, many phosphoERK-positive neurons were observed, most predominantly in lamina I and IIo of the ipsilateral dorsal horn. This staining was intensity and NMDA receptor dependent. Low-intensity stimuli or A-fiber input had no effect. Inhibition of ERK phosphorylation by a MEK inhibitor reduced the second phase of formalin-induced pain behavior, a measure of spinal neuron sensitization. ERK signaling within the spinal cord is therefore involved in generating pain hypersensitivity. Because of its rapid activation, this effect probably involves regulation of neuronal excitability without changes in transcription.

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Figure 1: Induction of ERK phosphorylation in the ipsilateral dorsal horn by intraplantar capsaicin injection.
Figure 2: Activation of pERK in the dorsal horn.
Figure 3: ERK activation is NMDA receptor dependent.
Figure 4: Aδ- and C-fiber-dependent activation of ERK in vitro.
Figure 5: Pre- and post-treatment with MEK inhibitor PD 98059 attenuates the behavioral response to intraplantar formalin.

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Acknowledgements

We thank Isabelle Decosterd for discussion and Raymond Schmoll and Sara Billet for technical support. Funded by NIH NS 38253-01 (C.J.W.), an unrestricted grant from Roche Bioscience, Human Frontier Science Program RG73/96 (C.J.W.) and Niigata University School of Medicine (H.B.).

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Correspondence to Ru-Rong Ji.

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Ji, RR., Baba, H., Brenner, G. et al. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci 2, 1114–1119 (1999). https://doi.org/10.1038/16040

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