Mammalian target of rapamycin in spinal cord neurons mediates hypersensitivity induced by peripheral inflammation.
mTOR, the mammalian target of rapamycin, is a serine-threonine kinase known to regulate cell proliferation and growth. mTOR has also been implicated in neuronal synaptic plasticity as well as in pain transmission in models of chemically induced and neuropathic pain. To date, the role of mTOR as a modulator of inflammatory pain has not been examined. In this study, we investigated the role of mTOR in Sprague-Dawley rats using the carrageenan model of inflammatory pain. mRNA of Ras homolog enriched in brain (Rheb), a GTPase that positively regulates mTOR activation, was significantly increased 2 h following carrageenan injection. Four hours after induction of inflammation phosphorylation (p) of p70S6 kinase (S6K), ribosomal protein S6 (S6) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) was increased, indicating mTOR activation. Inhibition of spinal mTOR with intrathecal (i.t.) injection of rapamycin (0.1-3 microg) led to a dose-dependent decrease in carrageenan-induced thermal hyperalgesia and a reduction of mechanical allodynia. In vitro studies confirmed rapamycin inhibition of the mTOR pathway. Carrageenan-induced activation of the mTOR pathway in rats was localized predominantly to dorsal horn neurons in the superficial lamina. Taken together, these data show that the mTOR pathway is activated in dorsal horn neurons during inflammatory pain, and that inhibition of spinal mTOR attenuates inflammation-induced thermal and tactile hypersensitivity. Hence, our study indicates that spinal mTOR is an important regulator of spinal sensitization and suggests that targeting mTOR may provide a new avenue for pain therapy.
Department of Physiology and Pharmacology, Karolinska Institutet, von Eulers väg 8, 171 77 Stockholm, Sweden.
E
E
Norsted Gregory
S
S
Codeluppi
J A
JA
Gregory
J
J
Steinauer
C I
CI
Svensson
D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008161:Lumbosacral Region; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D016716:PC12 Cells; D010146:Pain / Q000378:metabolism / Q000503:physiopathology*; D010147:Pain Measurement; D010766:Phosphorylation; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D017207:Rats, Sprague-Dawley; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C087693:Rheb protein, rat; D038601:Ribosomal Protein S6; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins