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The Journal of Neuroscience, August 20, 2008, 28(34):8568-8576; doi:10.1523/JNEUROSCI.2128-08.2008

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Behavioral/Systems/Cognitive
cGMP Produced by NO-Sensitive Guanylyl Cyclase Essentially Contributes to Inflammatory and Neuropathic Pain by Using Targets Different from cGMP-Dependent Protein Kinase I

Achim Schmidtko,¹ Wei Gao,¹ Peter König,² Sandra Heine,¹ Roberto Motterlini,³ Peter Ruth,⁴ Jens Schlossmann,⁵ Doris Koesling,⁶ Ellen Niederberger,¹ Irmgard Tegeder,¹ Andreas Friebe,⁶ and Gerd Geisslinger¹

¹Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany, ²Institut für Anatomie, Universität zu Lübeck, 23538 Lübeck, Germany, ³Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow HA1 3UJ, Middlesex, United Kingdom, ⁴Pharmakologie und Toxikologie, Pharmazeutisches Institut, 72076 Tübingen, Germany, ⁵Institut für Pharmakologie und Toxikologie, Universität Regensburg, 93040 Regensburg, Germany, and ⁶Medizinische Fakultät, Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, 44780 Bochum, Germany

Correspondence should be addressed to Dr. Achim Schmidtko, Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Email: Schmidtko{at}em.uni-frankfurt.de

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.

Key words: nitric oxide; natriuretic peptide; spinal cord; DRG; knock-out mice; pain behavior

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Received May 9, 2008; revised July 3, 2008; accepted July 17, 2008.

Correspondence should be addressed to Dr. Achim Schmidtko, Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Email: Schmidtko{at}em.uni-frankfurt.de

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