Lack of colonic inflammation-induced acute visceral hypersensitivity to colorectal distension in Na_v1.9 knockout mice

Tetrodotoxin-resistant voltage-gated sodium channels subtype 9 (Na_v1.9) 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_v1.9 channels on acute colonic inflammation-induced visceral hypersensitivity in conscious mice, using Na_v1.9 knockout (KO) mice. Colorectal distension (CRD)-induced visceral pain was assessed in conscious wild-type and Na_v1.9 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 (40 μg/animal). CRD was performed 5 h later, thereafter animals were euthanized and the colonic content of inflammatory mediators assessed. Normal pain responses were similar in Na_v1.9 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_v1.9 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_v1.9 KO mice, suggesting the presence of a similar acute inflammatory reaction in both groups of animals. These results suggest that Na_v1.9 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.