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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Cyclic GMP / adverse effects
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Cyclic GMP / analogs & derivatives
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Cyclic GMP / metabolism*
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Cyclic GMP / pharmacology
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Cyclic Nucleotide-Gated Cation Channels / deficiency
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Cyclic Nucleotide-Gated Cation Channels / genetics
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Cyclic Nucleotide-Gated Cation Channels / metabolism*
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Ganglia, Spinal / metabolism
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Gene Expression Regulation / drug effects
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Glial Fibrillary Acidic Protein / metabolism
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Inflammation / chemically induced
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Inflammation / complications*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microdissection
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Naphthalenes / metabolism
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Natriuretic Peptides / adverse effects
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Nitric Oxide / metabolism*
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Pain / drug therapy
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Pain / etiology*
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Pain / pathology
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Pain Measurement / drug effects
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Pain Measurement / methods
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Pain Perception / drug effects
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Peripheral Nervous System Diseases / drug therapy
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Peripheral Nervous System Diseases / pathology
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Physical Stimulation / adverse effects
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RNA, Messenger / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Spinal Cord / metabolism*
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Stathmin / metabolism
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Statistics, Nonparametric
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Thionucleotides / pharmacology
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Triazenes / pharmacology
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Vesicular Inhibitory Amino Acid Transport Proteins / metabolism
Substances
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1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene
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8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate
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Cnga3 protein, mouse
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Cyclic Nucleotide-Gated Cation Channels
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Enzyme Inhibitors
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Glial Fibrillary Acidic Protein
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Naphthalenes
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Natriuretic Peptides
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RNA, Messenger
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Stathmin
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Thionucleotides
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Triazenes
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Vesicular Inhibitory Amino Acid Transport Proteins
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Viaat protein, mouse
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Nitric Oxide
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8-((4-chlorophenyl)thio)cyclic-3',5'-GMP
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Cyclic GMP