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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Impey, S., Obrietan, K. & Storm, D. R. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 23, 11–14 (1999).
Cano, E. & Mahadeven, L. C. Parallel signal processing among mammalian MAPKs. Trends Biochem. Sci. 20, 117–122 (1995).
Seger, R. & Krebs, E. G. The MAPK signaling cascade. FASEB J. 9, 726–735 (1995).
Rosen, L. B., Ginty, D. D., Weber,, M. J. & Greeenberg, M. E. Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras. Neuron 12, 1207–1221 (1999).
Baraban, J. M., Fiore, R. S., Sanghera, J. S., Paddon, H. B. & Pelech, S. L. Identification of p42 mitogen-activated protein kinase as a tyrosine kinase substrate activated by maximal electroconvulsive shock in hippocampus. J. Neurochem. 60, 330–336 (1993).
Obrietan, K., Impey, S. & Storm, D. R. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nat. Neurosci. 1, 693–700 (1998).
English, J. D. & Sweatt, J. D. Activation of p42 mitogen-activated protein kinase in hippocampal long-term potentiation. J. Biol. Chem. 271, 24329–24332 (1996).
English, J. D. & Sweatt, J. D. A requirement for the mitogen-activated protein kinase cascade in hippocampal long-term potentiation. J. Biol. Chem. 272, 19103–19106 (1997).
Atkins, C. M., Selcher, J. C., Petraitis, J. J., Trzaskos, J. M. & Sweatt, J. D. The MAPK cascade is required for mammalian associative learning. Nat. Neurosci. 1, 602–609 (1998).
Impey, S. et al. Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21, 869–883 (1998).
Woolf, C. J. Evidence for a central component of post-injury pain hypersensitivity. Nature 306, 686–688 (1983).
Woolf, C. J. & Costigan, M. Transcriptional and post-translational plasticity and the regulation of inflammatory pain. Proc. Natl. Acad. Sci. USA 96, 7723–7730 (1999).
Simone, D. A., Baumann, T. K., Collins, J. G. & LaMotte, R. H. Sensitization of cat dorsal horn neurons to innocuous mechanical stimulation after intradermal injection of capsaicin. Brain Res. 486, 185–189 (1989).
Torebjork, H. E., Lundberg, L. E. R. & LaMotte, R. H. Central changes in processing of mechanoreceptor input in capsaicin-induced sensory hyperalgesia in humans. J. Physiol.(Lond.) 448, 765–780 (1992).
Dubuisson, D. & Dennis, S. G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine and brain stimulation in rats and cats. Pain 4, 161–174 (1977).
Dickenson, A. H. & Sullivan, A. F. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential responses to an intrathecal opiate administered pre or post formalin. Pain 30, 349–360 (1987).
Coderre, T. J., Vaccarino, A. L. & Melzack, R. Central nervous system plasticity in tonic pain response to subcutaneous formalin injection. Brain Res. 535, 155–158 (1990).
Yamamoto, T. & Yaksh, T. L. Comparison of the antinociceptive effects of pre- and posttreatment with intrathecal morphine and MK801, an NMDA antagonist, on the formalin test in the rat. Anesthesiology 77, 757–763 (1992).
Chen, L. & Huang, L.-Y. M. Protein kinase C reduces Mg_+ block of NMDA-receptor channels as a mechanism of modulation. Nature 356, 521–523 (1992).
Yu, X. M., Askalan, R., Keil, G. J. & Salter, M. W. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 275, 674–678 (1997).
Mannion, R. J. et al. Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc. Natl. Acad. Sci. USA 96, 9385–9390 (1999).
Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).
Swett, J. E. & Woolf, C. J. Somatotopic organization of primary afferent terminals in the superficial dorsal horn of the rat spinal cord. J. Comp. Neurol. 231, 66–71 (1985).
Bading, H. & Greeenberg, M. E. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253, 912–914 (1991).
Fiore, R. S., Murphy, T. H., Sanghera, J. S., Pelech, S. L. & Baraban, J. M. Activation of p42 mitogen-activated protein kinase by glutamate receptor stimulation in rat primary cortical cultures. J. Neurochem. 61, 1626–1633 (1993).
Baba, H. & Woolf, C. J. Peripheral inflammation facilitates Aβ fiber-mediated synaptic input to the substantia gelatinosa of the adult rat spinal cord. J. Neurosci. 19, 859–867 (1999).
Coderre, T. J. & Melzack, R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J. Neurosci. 12, 3665–3670 (1992).
Dickenson, A. H. & Sullivan, A. F. Peripheral origins and the central modulation of subcutaneous formalin-induced sensitivity of rat dorsal horn neurons. Neurosci. Lett. 83, 207–211 (1987).
Puig, S. & Sorkin, L. S. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 64, 345–355 (1995).
McCall, W. D., Tanner, K. D. & Levine, J. D. Formalin induces biphasic activity in C-fibers in the rat. Neurosci. Lett. 208, 45–48 (1996).
Henry, J. L., Yashpal, K., Pitcher, G. M., Chabot, J.-G. & Coderre, T. J. Evidence for tonic activation of NK-1 receptors during the second phase of the formalin test in the rat. J. Neurosci. 19, 6588–6598 (1999).
Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T. & Saltiel, A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase in vitro and in vivo. J. Biol. Chem. 270, 27489–27494 (1995).
Qiu, M. S. & Green, S. H. PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity. Neuron 9, 705–717 (1992).
Sgambato, V., Pages, C., Rogard, M., Besson, M. J. & Caboche, J. Extracellular signal-regulated kinase (ERK) controls immediate early gene induction on corticostrital stimulation. J. Neurosci. 18, 8814–8825 (1998).
Molliver, D. C. et al. IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19, 849–861 (1997).
Snider, W. D. & McMahon, S. B. Tackling pain at the source: new ideas about nociceptors. Neuron 20, 629–632 (1998).
Sun, H., Charles, C. H., Lau, L. F. & Tonks, N. K. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell 75, 487–493 (1993).
Michael, G. J. et al. Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in Trk-A expressing dorsal root ganglion cells and in their central terminals within the spinal cord. J. Neurosci. 17, 8476–8490 (1997).
Woolf, C. J., Mannion, R. J. & Neumann, S. Null mutations lacking substance: Elucidating pain mechanisms by genetic pharmacology. Neuron 20, 1063–1066 (1998).
Woolf, C. J. & Thompson, S. W. N. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain 44, 293–299 (1991).
Sanes, J. R. & Lichtman, J. W. Can molecules explain long-term potentiation? Nat. Neurosci. 2, 597–604 (1999).
Xing, J., Ginty, D. D. & Greenberg, M. E. Coupling of the Ras-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273, 959–963 (1996).
Martin, K. C. et al. MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Neuron 18, 899–912 (1997).
Ji, R. R. & Rupp, F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J. Neurosci. 17, 1776–1785 (1997).
Messersmith, D. J., Kim, D. J. & Iadarola, M. J. Transcription factor regulation of prodynorphin gene expression following rat hindpaw inflammation. Mol. Brain Res. 53, 260–269 (1998).
Hunt, S. P., Pini, A. & Evan, G. Induction of c-fos-like protein in spinal cord neurones following sensory stimulation. Nature 328, 632–634 (1987).
Dubner, R. & Ruda, M. A. Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci. 15, 96–103 (1992).
McCarson, K. E. & Krause, J. E. NK-1 and NK-3 type tachykinin receptor mRNA expression in the rat spinal cord dorsal horn is increased during adjuvant or formalin-induced nociception. J. Neurosci. 14, 712–720 (1994).
Ji, R. R., Zhang, X., Wiesenfeld-Hallin, Z. & Hokfelt, T. Expression of neuropeptide and neuropeptide Y (Y1) receptor mRNA in rat spinal cord and dorsal root ganglia following peripheral tissue inflammation. J. Neurosci. 14, 6423–6434 (1994).
Ji, R. R. et al. Central and peripheral expression of galanin in response to inflammation. Neuroscience 68, 563–576 (1995).
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.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/16040
This article is cited by
-
Shank2 identifies a subset of glycinergic neurons involved in altered nociception in an autism model
Molecular Autism (2023)
-
The potent analgesia of intrathecal 2R, 6R-HNK via TRPA1 inhibition in LF-PENS-induced chronic primary pain model
The Journal of Headache and Pain (2023)
-
CGRP-dependent sensitization of PKC-δ positive neurons in central amygdala mediates chronic migraine
The Journal of Headache and Pain (2022)
-
Harnessing bacterial toxins to treat pain
Nature Neuroscience (2022)
-
Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2+ DRG sensory neurons
Nature Neuroscience (2022)