title: Spinal phosphinositide 3-kinase-Akt-mammalian target of rapamycin signaling cascades in inflammation-induced hyperalgesia.
abstract: Phosphinositide 3-kinase (PI3K), Akt, and their downstream kinase, mammalian target of rapamycin (mTOR), are implicated in neural plasticity. The functional linkages of this signaling cascade in spinal dorsal horn and their role in inflammatory hyperalgesia have not been elucidated. In the present work, we identified the following characteristics of this cascade. (1) Local inflammation led to increase in rat dorsal horn phosphorylation (activation) of Akt (pAkt) and mTOR (pmTOR), as assessed by Western blotting and immunocytochemistry. (2) Increased pAkt and pmTOR were prominent in neurons in laminae I, III, and IV, whereas pmTOR and its downstream targets (pS6, p4EBP) were also observed in glial cells. (3) Intrathecal treatment with inhibitors to PI3K or Akt attenuated Formalin-induced second-phase flinching behavior, as well as carrageenan-induced thermal hyperalgesia and tactile allodynia. (4) Intrathecal rapamycin (an mTORC1 inhibitor) displayed anti-hyperalgesic effect in both inflammatory pain models. Importantly, intrathecal wortmannin at anti-hyperalgesic doses reversed the evoked increase not only in Akt but also in mTORC1 signaling (pS6/p4EBP). (5) pAkt and pmTOR are expressed in neurokinin 1 receptor-positive neurons in laminae I-III after peripheral inflammation. Intrathecal injection of Substance P activated this cascade (increased phosphorylation) and resulted in hyperalgesia, both of which effects were blocked by intrathecal wortmannin and rapamycin. Together, these findings reveal that afferent inputs trigged by peripheral inflammation initiate spinal activation of PI3K-Akt-mTOR signaling pathway, a component of which participates in neuronal circuits of facilitated pain processing.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093, USA. q1xu@ucsd.edu
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Xu
authors.forename: Bethany
authors.initials: B
authors.lastname: Fitzsimmons
authors.forename: Joanne
authors.initials: J
authors.lastname: Steinauer
authors.forename: Audrey
authors.initials: A
authors.lastname: O'Neill
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Hua
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D000730:Androstadienes / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002351:Carrageenan / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005557:Formaldehyde / Q000009:adverse effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010147:Pain Measurement; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology; D013116:Spinal Cord / Q000201:enzymology* / Q000473:pathology; D018709:Statistics, Nonparametric; D013373:Substance P / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002351:Carrageenan; D004791:Enzyme Inhibitors; D005557:Formaldehyde; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D013373:Substance P; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; C546845:mTOR protein, rat