title: mTOR and its downstream pathway are activated in the dorsal root ganglion and spinal cord after peripheral inflammation, but not after nerve injury.
abstract: Protein translation controlled through activation of mammalian target of rapamycin (mTOR) participates in many physiological and pathological processes. However, whether such activation is required for chronic pain is still unknown. Here, we examined activation of the mTOR signaling pathway during complete Freund's adjuvant (CFA)-induced chronic inflammatory pain and L5 spinal nerve ligation (SNL)-induced neuropathic pain in rats. Western blot analysis showed significantly increased levels of phosphorylated mTOR (p-mTOR) and phosphorylated p70S6 kinase 1 (p-S6K1, a downstream effector of mTOR) in the ipsilateral L4/5 spinal cord 2h, 1 day, 3 days, and 7 days after intraplantar CFA injection and in the ipsilateral L4/5 dorsal root ganglions (DRGs) 1 and 3 days after CFA injection. Immunohistochemistry also demonstrated increases in number of p-mTOR-labeled neurons in the ipsilateral L4/5 DRGs and in density of p-mTOR-labeled immunoreactivity in the ipsilateral L4/5 superficial dorsal horn 1 day after CFA injection. Moreover, intrathecal administration of rapamycin, a selective inhibitor of mTOR, significantly blocked CFA-induced mechanical allodynia and thermal hyperalgesia 1 day post-CFA injection. Interestingly, expression of neither p-mTOR nor p-S6K1 was markedly altered on days 3, 7, or 14 after L5 SNL in L5 spinal cord or DRG. These findings indicate that in DRG and spinal cord, mTOR and S6K1 are activated during chronic inflammatory pain, but not during neuropathic pain. Our results strongly suggest that mTOR and its downstream pathway contribute to the development of chronic inflammatory pain.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 1721 East Madison Street, 370 Ross, Baltimore, MD 21205, USA.
authors.forename: Lingli
authors.initials: L
authors.lastname: Liang
authors.forename: Bo
authors.initials: B
authors.lastname: Tao
authors.forename: Longchang
authors.initials: L
authors.lastname: Fan
authors.forename: Myron
authors.initials: M
authors.lastname: Yaster
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009437:Neuralgia; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000473:pathology*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism*; D013127:Spinal Nerves / Q000473:pathology; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D005620:Freund's Adjuvant; C546845:mTOR protein, rat; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus