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.