title: Lack of colonic-inflammation-induced acute visceral hypersensitivity to colorectal distension in Na(v)1.9 knockout mice.
abstract: Tetrodotoxin-resistant voltage-gated sodium channels subtype 9 (Na(v)1.9) are expressed in small-diameter dorsal root ganglion neurons and have been involved in persistent somatic hyperalgesic responses associated with inflammation. We assessed the role of Na(v)1.9 channels on acute colonic inflammation-induced visceral hypersensitivity in conscious mice, using Na(v)1.9 knockout (KO) mice. Colorectal distension (CRD)-induced visceral pain was assessed in conscious wild-type and Na(v)1.9 KO mice (C57Bl/6 background). The mechanical activity of the abdominal muscles during isobaric colorectal distension was used as a measure of visceral pain. Acute colonic inflammation was induced by intracolonic administration of the toll-like receptor (TLR) 7 activator, R-848 (40mug/animal). CRD was performed 5h later, thereafter animals were euthanized and the colonic content of inflammatory mediators assessed. Normal pain responses were similar in Na(v)1.9 KO and wild-type mice. In wild-type mice, R-848 administration increased the response to phasic CRD by 62% compared with vehicle-treated animals (vehicle: 0.16+/-0.04, R-848: 0.26+/-0.03, n=6-7, P<0.05). However, in Na(v)1.9 KO mice, intracolonic R-848 did not affect the response to CRD (0.11+/-0.02, n=7) compared to animals treated with vehicle (0.17+/-0.03, n=5; P>0.05). After R-848 administration, the colonic content of pro-inflammatory cytokines was increased in similar proportion in wild type and Na(v)1.9 KO mice, suggesting the presence of a similar acute inflammatory reaction in both groups of animals. These results suggest that Na(v)1.9 channels do not significantly contribute to normal visceral pain responses to acute colonic mechanical stimulation but may be important for the development of inflammation-related acute visceral hyperalgesic responses.
authors.affiliation: Integrative Pharmacology, Gastrointestinal Biology, AstraZeneca R&D Mölndal, Mölndal, Sweden. vicente.martinez@astrazeneca.com
authors.forename: V
authors.initials: V
authors.lastname: Martinez
authors.forename: S
authors.initials: S
authors.lastname: Melgar
mesh_terms: D000208:Acute Disease; D000818:Animals; D002404:Catheterization / Q000009:adverse effects; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D003106:Colon / Q000737:chemistry; D005260:Female; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D007093:Imidazoles / Q000633:toxicity; D018836:Inflammation Mediators / Q000032:analysis; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012007:Rectum / Q000737:chemistry; D012008:Recurrence; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013314:Stress, Mechanical; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors
chemical_list: D007093:Imidazoles; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C491885:Scn11a protein, mouse; D015222:Sodium Channels; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C402365:resiquimod