The role of Substance P and its signaling pathways in central sensitization

Central sensitization of nociceptive dorsal horn neurons is an underlying mechanism of behavioral phenotype, such as secondary hyperalgesia. Substance P (SP) is regarded as an important neuropeptide and mainly exists in primary afferent fibers in the superficial dorsal horn. Release of SP in the dorsal horn can be triggered in response to peripheral noxious stimuli. After release, substance P binds with neurokinin-1 (NK-1) receptors, which are abundantly expressed in the superficial layers of the dorsal horn. The first part of this study investigates the change in release of SP in the dorsal horn following intradermal injection of capsaicin and evaluates the role of NK-1 activation in a capsaicin-induced exaggerated pain state in rats. A significant increase of SP in rat dorsal horn was observed after capsaicin injection. Electrophysiological and behavioral results showed that NK-1 activation is required for the development of central sensitization.\r\nRecent evidence has also demonstrated that several important protein kinases are involved in central sensitization evoked by SP. The second part of this study is to investigate the contribution of secondary messengers, such as calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC), to spinal cord pain mechanisms, following NK-1 activation. Spinothalamic tract (STT) cells in lumbar segments of the rat spinal cord were retrogradely labeled with fluorogold (FG). Colocalization of NK-1 receptors with phosphorylated CaMKII alpha (pCaMKII alpha), or with PKC gamma, was observed in STT neurons, as well as in unidentified dorsal horn neurons. Moreover, intrathecal injection of SP induced increased expression of pCaMKII alpha and PKC gamma in the superficial dorsal horn. Also, it was demonstrated that activation of CaMKII and PKC plays an important role in SP-mediated pain transduction. \r\n This study helps elucidate the involvement of the NK-1 receptor and its signaling pathways in the nociceptive processing following peripheral inflammation. Hopefully, the results will lead to further understanding of central sensitization, and this will contribute to the improvement in pain therapy.\r\n