title: mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK.
abstract: Mammalian target of rapamycin complex 1 (mTORC1) inhibitors are extensively used as immunosuppressants to prevent transplant rejection and in treatment of certain cancers. In patients, chronic treatment with rapamycin or its analogues (rapalogues) has been reported to lead to sensory hypersensitivity and pain conditions via an unknown mechanism. Here, we show that pharmacological or genetic inhibition of mTORC1 activates the extracellular signal-regulated kinase (ERK) pathway in sensory neurons via suppression of S6K1 to insulin receptor substrate 1 negative feedback loop. As a result, increased ERK activity induces sensory neuron sensitization, mechanical hypersensitivity, and spontaneous pain. The clinically available adenosine monophosphate-activated protein kinase activator, metformin, which is an antidiabetic drug, prevents rapamycin-induced ERK activation and the development of mechanical hypersensitivity and spontaneous pain. Taken together, our findings demonstrate that activation of the ERK pathway in sensory neurons as a consequence of mTORC1 inhibition leads to the development of pain. Importantly, this effect is abolished by co-treatment with metformin, thus providing a potential treatment option for rapalogue-evoked pain. Our findings highlight the physiological relevance of feedback signaling through mTORC1 inhibition and have important implications for development of pain therapeutics that target the mTOR pathway.
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
authors.forename: Ohannes K
authors.initials: OK
authors.lastname: Melemedjian
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sorge
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.forename: Marina N
authors.initials: MN
authors.lastname: Asiedu
authors.forename: Arely
authors.initials: A
authors.lastname: Valdez
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
authors.forename: Gregory
authors.initials: G
authors.lastname: Dussor
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
mesh_terms: D000818:Animals; D015536:Down-Regulation; D004789:Enzyme Activation; D025461:Feedback, Physiological; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus