Involvement of protein kinase C in 5-HT-evoked thermal hyperalgesia and spinal fos protein expression in the rat

The present study was designed to characterize nociceptive response induced by 5-hydroxytryptamine (5-HT) and to investigate effects of inhibition of protein kinase C (PKC) in the periphery on noxious stimulus-evoked activity of the secondary neurons in the spinal cord. Subcutaneous injection of 5-HT (50 μg) and α-methylserotonin (α-m-5-HT, 5-HT2A receptor agonist, 50 μg) into the unilateral hindpaw evoked significant decreases in paw withdrawal latency (PWL). The 5-HT-induced hyperalgesia was abolished by ketanserin (5-HT2A antagonist, 10 μg, intraplantarly or i.pl.), but not by WAY100635 (5-HT1A antagonist, 100 μg, i.pl.). 5-HT and α-m-5-HT also evoked numerous expressions of c-Fos-like immunoreactivity (c-fos-LI) in the ipsilateral dorsal horn (predominantly laminae I-II) of the lumbar spinal cord. However, treatment with 8-OH-DPAT (5-HT1A receptor agonist, 100 μg, i.pl.) elicited only moderate thermal hyperalgesia and very limited expression of spinal c-fos-LI. Intraplantar chelerythrine (2, 6 or 10 μg), a PKC inhibitor, dose-dependently attenuated the hyperalgesia evoked by α-m-5-HT. Chelerythrine (10 μg, i.pl.) also completely prevented the development of hyperalgesia evoked by 5-HT but not by 8-OH-DPAT. Furthermore, pretreatment with chelerythrine significantly inhibited the expressions of c-fos-LI evoked by α-m-5-HT in laminae I-VI and by 5-HT in laminae I-II. These results demonstrate that PKC activation was involved in the development of nociceptive responses elicited by 5-HT and activation of peripheral 5-HT2A, but not 5-HT1A, receptors. The study also provides evidence at a cellular level that inhibition of PKC in the periphery suppresses the 5-HT-evoked neuronal activity in the central nervous system.