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Distinct functions of soluble guanylyl cyclase isoforms NO-GC1 and NO-GC2 in inflammatory and neuropathic pain processing

Petersen, Jonasa,b; Mergia, Evanthiac; Kennel, Leaa; Drees, Oliverb; Steubing, Rebecca Dorotheeb; Real, Catherine Isabellb; Kallenborn-Gerhardt, Wiebkea; Lu, Ruiruia,b; Friebe, Andreasd; Koesling, Dorisc; Schmidtko, Achima,b,*

doi: 10.1097/j.pain.0000000000001440
Research Paper

A large body of evidence indicates that nitric oxide (NO)/cGMP signaling essentially contributes to the processing of chronic pain. In general, NO-induced cGMP formation is catalyzed by 2 isoforms of guanylyl cyclase, NO-sensitive guanylyl cyclase 1 (NO-GC1) and 2 (NO-GC2). However, the specific functions of the 2 isoforms in pain processing remain elusive. Here, we investigated the distribution of NO-GC1 and NO-GC2 in the spinal cord and dorsal root ganglia, and we characterized the behavior of mice lacking either isoform in animal models of pain. Using immunohistochemistry and in situ hybridization, we demonstrate that both isoforms are localized to interneurons in the spinal dorsal horn with NO-GC1 being enriched in inhibitory interneurons. In dorsal root ganglia, the distribution of NO-GC1 and NO-GC2 is restricted to non-neuronal cells with NO-GC2 being the major isoform in satellite glial cells. Mice lacking NO-GC1 demonstrated reduced hypersensitivity in models of neuropathic pain, whereas their behavior in models of inflammatory pain was normal. By contrast, mice lacking NO-GC2 exhibited increased hypersensitivity in models of inflammatory pain, but their neuropathic pain behavior was unaltered. Cre-mediated deletion of NO-GC1 or NO-GC2 in spinal dorsal horn neurons recapitulated the behavioral phenotypes observed in the global knockout. Together, these results indicate that cGMP produced by NO-GC1 or NO-GC2 in spinal dorsal horn neurons exert distinct, and partly opposing, functions in chronic pain processing.

The in vivo relevance of the 2 NO-GC isoforms for pain processing was investigated using global and conditional knockout mice.

aPharmakologisches Institut für Naturwissenschaftler, Goethe-Universität, Frankfurt am Main, Germany

bInstitut für Pharmakologie und Toxikologie, ZBAF, Universität Witten/Herdecke, Witten, Germany

cInstitut für Pharmakologie und Toxikologie, Ruhr-Universität, Bochum, Germany

dPhysiologisches Institut, Universität Würzburg, Würzburg, Germany

Corresponding author. Address: Pharmakologisches Institut für Naturwissenschaftler, Goethe-Universität, Fachbereich Biochemie, Chemie und Pharmazie, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany. Tel.: +49 69 798 29373; fax: +49 69 798 29374. E-mail address: (A. Schmidtko).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received April 26, 2018

Received in revised form September 12, 2018

Accepted November 02, 2018

© 2019 International Association for the Study of Pain
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