Isoform Specific Inhibition for Treatment of Pain and Reduction of Anesthetic Threshold.

摘要

Several lines of evidence have shown a role for the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway in the development of spinal hyperalgesia. However, the roles of effectors for cGMP are not fully understood in the processing of pain in the spinal cord. cGMP-dependent protein kinase (PKG) Ialpha but not PKGIbeta was localized in the neuronal bodies and processes, and was distributed primarily in the superficial laminae of the spinal cord. Intrathecal administration of an inhibitor of PKGIalpha, Rp-8-((4-Chlorophenyl)thio-)-cGMPS triethylamine, produces significant antinociception. Moreover, PKGIalpha protein expression was dramatically increased in the lumbar spinal cord after noxious stimulation. This upregulation of PKGIalpha expression was completely blocked not only by a neuronal NO synthase inhibitor, and a soluble guanylate cyclase inhibitor, but also by an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. Noxious stimulation not only initially activates but also later upregulates PKGIalpha expression in the superficial laminae via an NMDA-No-cGMP signaling pathway, suggesting that PKGI.alpha. plays an important role in the central mechanism of inflammatory hyperalgesia in the spinal cord.