title: Systemic inhibition of the mammalian target of rapamycin (mTOR) pathway reduces neuropathic pain in mice.
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.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland Department of Physiology, University of Bristol, Bristol BS8 1TD, UK Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Obara
authors.forename: Keri K
authors.initials: KK
authors.lastname: Tochiki
authors.forename: Sandrine M
authors.initials: SM
authors.lastname: Géranton
authors.forename: Fiona B
authors.initials: FB
authors.lastname: Carr
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Lumb
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunt
mesh_terms: D000818:Animals; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; C401859:temsirolimus; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus