A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states

Sandrine M Géranton, Lydia Jiménez-Díaz, Carole Torsney, Keri K Tochiki, Sarah A Stuart, J Lianne Leith, Bridget M Lumb, Stephen P Hunt

Research output: Contribution to journalArticle (Academic Journal)peer-review

122 Citations (Scopus)

Abstract

Translational control through the mammalian target of rapamycin (mTOR) is critical for synaptic plasticity, cell growth, and axon guidance. Recently, it was also shown that mTOR signaling was essential for the maintenance of the sensitivity of subsets of adult sensory neurons. Here, we show that persistent pain states, but not acute pain behavior, are substantially alleviated by centrally administered rapamycin, an inhibitor of the mTOR pathway. We demonstrate that rapamycin modulates nociception by acting on subsets of primary afferents and superficial dorsal horn neurons to reduce both primary afferent sensitivity and central plasticity. We found that the active form of mTOR is present in a subpopulation of myelinated dorsal root axons, but rarely in unmyelinated C-fibers, and heavily expressed in the dorsal horn by lamina I/III projection neurons that are known to mediate the induction and maintenance of pain states. Intrathecal injections of rapamycin inhibited the activation of downstream targets of mTOR in dorsal horn and dorsal roots and reduced the thermal sensitivity of A-fibers. Moreover, in vitro studies showed that rapamycin increased the electrical activation threshold of Adelta-fibers in dorsal roots. Together, our results imply that central rapamycin reduces neuropathic pain by acting both on an mTOR-positive subset of A-nociceptors and lamina I projection neurons and suggest a new pharmacological route for therapeutic intervention in persistent pain states.

Translated title of the contributionA rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states
Original languageEnglish
Pages (from-to)15017 - 15027
Number of pages11
JournalJournal of Neuroscience
Volume29
Issue number47
DOIs
Publication statusPublished - 25 Nov 2009

Keywords

  • Afferent Pathways
  • Animals
  • Hyperalgesia
  • Immunosuppressive Agents
  • Male
  • Nerve Fibers, Myelinated
  • Nociceptors
  • Pain
  • Pain Measurement
  • Pain Threshold
  • Peripheral Nervous System Diseases
  • Posterior Horn Cells
  • Protein Kinases
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Sciatic Neuropathy
  • Sirolimus
  • Spinal Nerve Roots
  • Spinothalamic Tracts
  • TOR Serine-Threonine Kinases

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