Involvement of cGMP in Nociceptive Processing by and Sensitization of Spinothalamic Neurons in Primates

Abstract

Central sensitization of spinothalamic tract (STT) neurons in anesthetized monkeys after intradermal injection of capsaicin depends in part on disinhibition. Protein kinase C is suggested to participate in this process. The present study shows that the nitric oxide-cGMP (NO-cGMP) signal transduction system also contributes to sensitization of wide dynamic range (WDR) STT neurons located in the deep dorsal horn. The NO-cGMP system was activated by microdialysis administration into the dorsal horn of 8-bromo-cGMP, an analog of cGMP. Sensitization of STT cells by 8-bromo-cGMP increased the responses of deep WDR STT cells to both weak and strong mechanical stimulation of the skin and simultaneously attenuated the inhibition of the same neurons produced by stimulation in the periaqueductal gray (PAG). In contrast, WDR STT cells in the superficial dorsal horn and high-threshold (HT) STT cells in superficial or deep layers showed reduced responses to mechanical stimulation of the skin after infusion of 8-bromo-cGMP, and PAG inhibition of these neurons was unaffected. Sensitization of STT cells and the attenuation of PAG inhibition induced by intradermal injection of capsaicin were prevented by preteatment of the dorsal horn with a guanylate cyclase inhibitor, 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The results support the hypothesis that activation of the NO-cGMP signal transduction system contributes to the sensitization of WDR STT neurons in the deep dorsal horn and helps explain why intradermal capsaicin injections often fail to sensitize superficial and HT STT cells. The results also support the idea that sensitization of STT cells is produced in part by disinhibition.