title: CNGA3: a target of spinal nitric oxide/cGMP signaling and modulator of inflammatory pain hypersensitivity.
abstract: A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing. In situ hybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3(-/-) mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover, CNGA3(-/-) mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Heine
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Wiebke
authors.initials: W
authors.lastname: Kallenborn-Gerhardt
authors.forename: Ruirui
authors.initials: R
authors.lastname: Lu
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Lim
authors.forename: Jessica
authors.initials: J
authors.lastname: Weiland
authors.forename: Domenico
authors.initials: D
authors.lastname: Del Turco
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Achim
authors.initials: A
authors.lastname: Schmidtko
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D006152:Cyclic GMP / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D042282:Microdissection; D009281:Naphthalenes / Q000378:metabolism; D045265:Natriuretic Peptides / Q000009:adverse effects; D009569:Nitric Oxide / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D058748:Pain Perception / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000473:pathology; D010812:Physical Stimulation / Q000009:adverse effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism*; D050777:Stathmin / Q000378:metabolism; D018709:Statistics, Nonparametric; D013873:Thionucleotides / Q000494:pharmacology; D014226:Triazenes / Q000494:pharmacology; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: C114535:1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene; C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; C518237:Cnga3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009281:Naphthalenes; D045265:Natriuretic Peptides; D012333:RNA, Messenger; D050777:Stathmin; D013873:Thionucleotides; D014226:Triazenes; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D009569:Nitric Oxide; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D006152:Cyclic GMP