Spinal protein kinase M £ underlies the maintenance mechanism of persistent nociceptive sensitization

Marina N. Asiedu, Dipti V. Tillu, Ohannes K. Melemedjian, Adia Shy, Raul Sanoja, Bryce Bodell, Sourav Ghosh, Frank Porreca, Theodore J. Price

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Abstract

Sensitization of the pain pathway is believed to promote clinical pain disorders. We hypothesized that the persistence of a sensitized state in the spinal dorsal horn might depend on the activity of protein kinase M £ (PKM£), an essential mechanism of late long-term potentiation (LTP). To test this hypothesis, we used intraplantar injections of interleukin-6 (IL-6) in mice to elicit a transient allodynic state that endured ~3 d. After the resolution of IL-6-induced allodynia, a subsequent intraplantar injection of prostaglandin E2 (PGE2) or intrathecal injection of the metabotropic glutamate receptor 1/5 (mGluR1/5) agonist DHPG (dihydroxyphenylglycol) precipitated allodynia and/or nocifensive responses. Intraplantar injection of IL-6 followed immediately by intrathecal injection of a PKM£ inhibitor prevented the expression of subsequent PGE2-induced allodynia. Inhibitors of protein translation were effective in preventing PGE2-induced allodynia when given immediately after IL-6, but not after the initial allodynia had resolved. In contrast, spinal PKM£ inhibition completely abolished both prolonged allodynia to hindpaw PGE2 and enhanced nocifensive behaviors evoked by intrathecal mGluR1/5 agonist injection after the resolution of IL-6-induced allodynia. Moreover, spinal PKM£ inhibition prevented the enhanced response to subsequent stimuli following resolution of hypersensitivity induced by plantar incision. The present findings demonstrate that the spinal cord encodes an engram for persistent nociceptive sensitization that is analogous to molecular mechanisms of late LTP and suggest that spinally directed PKM£ inhibitors may offer therapeutic benefit for injury-induced pain states.

Original languageEnglish (US)
Pages (from-to)6646-6653
Number of pages8
JournalJournal of Neuroscience
Volume31
Issue number18
DOIs
Publication statusPublished - May 4 2011

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Asiedu, M. N., Tillu, D. V., Melemedjian, O. K., Shy, A., Sanoja, R., Bodell, B., ... Price, T. J. (2011). Spinal protein kinase M £ underlies the maintenance mechanism of persistent nociceptive sensitization. Journal of Neuroscience, 31(18), 6646-6653. https://doi.org/10.1523/JNEUROSCI.6286-10.2011