Systemic inhibition of the mammalian target of rapamycin (mTOR) pathway reduces neuropathic pain in mice

Ilona Obara*, Keri K Tochiki, Sandrine M Géranton, Fiona B Carr, Bridget M Lumb, Qingsong Liu, Stephen P Hunt

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

65 Citations (Scopus)

Abstract

The management of neuropathic pain is unsatisfactory, and new treatments are required. Because the sensitivity of a subset of fast-conducting primary afferent nociceptors is thought to be regulated by the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, selectively targeting mTORC1 represents a new strategy for the control of chronic pain. Here we show that activated mTOR was expressed largely in myelinated sensory fibers in mouse and that inhibiting the mTORC1 pathway systemically alleviated mechanical hypersensitivity in mouse models of inflammatory and neuropathic pain. Specifically, systemic administration of mTORC1 inhibitor temsirolimus (CCI-779), both acutely (25 mg/kg i.p.) and chronically (4 daily 25 mg/kg i.p.), inhibited the mTORC1 pathway in sensory axons and the spinal dorsal horn and reduced mechanical and cold hypersensitivity induced by nerve injury. Moreover, systemic treatment with CCI-779 also reduced mechanical but not heat hypersensitivity in an inflammatory pain state. This treatment did not influence nociceptive thresholds in naive or sham-treated control animals. Also, there was no evidence for neuronal toxicity after repeated systemic treatment with CCI-779. Additionally, we show that acute and chronic i.p. administration of Torin1 (20 mg/kg), a novel ATP-competitive inhibitor targeting both mTORC1 and mTORC2 pathways, reduced the response to mechanical and cold stimuli in neuropathic mice. Our findings emphasize the importance of the mTORC1 pathway as a regulator of nociceptor sensitivity and therefore as a potential target for therapeutic intervention, particularly in chronic pain.
Original languageEnglish
Pages (from-to)2582-2595
Number of pages14
JournalPAIN
Volume152
Issue number11
DOIs
Publication statusPublished - Nov 2011

Bibliographical note

Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Keywords

  • Inflammatory pain
  • Local translation
  • mTOR
  • Neuropathic pain
  • Temsirolimus (CCI-779)
  • Torin1
  • INDUCED THERMAL HYPERALGESIA
  • SPARED NERVE INJURY
  • 3-KINASE-AKT-MAMMALIAN TARGET
  • SYNAPTIC PLASTICITY
  • SIGNALING PATHWAY
  • LOCAL TRANSLATION
  • PROTEIN-SYNTHESIS
  • ANALOG CCI-779
  • GROWTH-FACTOR
  • MOUSE MODELS

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    Obara, I., Tochiki, K. K., Géranton, S. M., Carr, F. B., Lumb, B. M., Liu, Q., & Hunt, S. P. (2011). Systemic inhibition of the mammalian target of rapamycin (mTOR) pathway reduces neuropathic pain in mice. PAIN, 152(11), 2582-2595. https://doi.org/10.1016/j.pain.2011.07.025