We investigated the involvement of the
protein kinase B/Akt (PKB/Akt) signaling pathway in the mechanical
hypersensitivity induced in rats by
capsaicin.
Intradermal injection of
capsaicin results in activation of PKB/Akt in the lumbar spinal cord, most prominently in the dorsal horn, starting by 5 min after
capsaicin injection and lasting at least 1h. The activated PKB/Akt in the spinal cord is in neurons, since phospho-PKB/Akt (p-PKB/Akt) colocalizes with the neuronal marker, neuronal-specific
nuclear protein (NeuN). The mechanical
hypersensitivity is shown by the enhanced paw withdrawal frequency to applications of von Frey filaments with different bending forces (30, 100, 200 mN) on the rat paw. Pre-treatment with several different PKB/Akt inhibitors, including SH-6,
Akt inhibitor IV, and Akt inhibitor V, blocked the mechanical
hypersensitivity induced by
intradermal injection of
capsaicin, a measure of spinal cord central sensitization. Two structurally unrelated
phosphoinositide 3-Kinase (PI3K, upstream of PKB/Akt) inhibitors,
Wortmannin and
LY294002, also prevented the mechanical
hypersensitivity induced by
intradermal injection of
capsaicin. Furthermore, post-treatment with the PI3K inhibitor,
Wortmannin, or PKB/Akt inhibitors, such as
NL-71-101, SH-6,
Akt inhibitor IV, and inhibitor V significantly reduced the established mechanical
hypersensitivity induced by
capsaicin. The PKB/Akt signaling pathway in the spinal cord is therefore involved in
pain hypersensitivity.