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.