cGMP produced by NO-sensitive guanylyl cyclase essentially contributes to inflammatory and neuropathic pain by using targets different from cGMP-dependent protein kinase I.
A large body of evidence indicates that the release of nitric oxide (NO) is crucial for the central sensitization of pain pathways during both inflammatory and neuropathic pain. Here, we investigated the distribution of NO-sensitive guanylyl cyclase (NO-GC) in the spinal cord and in dorsal root ganglia, and we characterized the nociceptive behavior of mice deficient in NO-GC (GC-KO mice). We show that NO-GC is distinctly expressed in neurons of the mouse dorsal horn, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. GC-KO mice exhibited a considerably reduced nociceptive behavior in models of inflammatory or neuropathic pain, but their responses to acute pain were not impaired. Moreover, GC-KO mice failed to develop pain sensitization induced by intrathecal administration of drugs releasing NO or carbon monoxide. Surprisingly, during spinal nociceptive processing, cGMP produced by NO-GC may activate signaling pathways different from cGMP-dependent protein kinase I (cGKI), whereas cGKI can be activated by natriuretic peptide receptor-B dependent cGMP production. Together, our results provide evidence that NO-GC is crucially involved in the central sensitization of pain pathways during inflammatory and neuropathic pain.
Schmidtko
Achim
A
Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany. Schmidtko@em.uni-frankfurt.de
Gao
Wei
W
König
Peter
P
Heine
Sandra
S
Motterlini
Roberto
R
Ruth
Peter
P
Schlossmann
Jens
J
Koesling
Doris
D
Niederberger
Ellen
E
Tegeder
Irmgard
I
Friebe
Andreas
A
Geisslinger
Gerd
G
D000818:Animals; D001522:Behavior, Animal; D002248:Carbon Monoxide / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis*; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000172:deficiency / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology / Q000523:psychology; D009619:Nociceptors / Q000503:physiopathology; D010146:Pain / Q000209:etiology / Q000378:metabolism* / Q000523:psychology; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013116:Spinal Cord / Q000378:metabolism*; D014018:Tissue Distribution
D018160:Receptors, Cytoplasmic and Nuclear; D002248:Carbon Monoxide; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP