Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice.

TLDR: There is an essential role for Nav1.8 in mediating spontaneous activity in sensitized nociceptors in the absence of additional stimuli, according to a visceral model of tonic noxious chemical stimulation, cyclophosphamide cystitis.

Abstract: The tetrodotoxin-resistant sodium channel α subunit Nav1.8 is expressed exclusively in primary sensory neurons and is proposed to play an important role in sensitization of nociceptors. Here we compared visceral pain and referred hyperalgesia in Nav1.8-null mice and their wild-type littermates in five tests that differ in the degree to which behavior depends on spontaneous, ongoing firing in sensitized nociceptors. Nav1.8-null mice showed normal nociceptive behavior provoked by acute noxious stimulation of abdominal viscera (intracolonic saline or intraperitoneal acetylcholine). However, Nav1.8-null mutants showed weak pain and no referred hyperalgesia to intracolonic capsaicin, a model in which behavior is sustained by ongoing activity in nociceptors sensitized by the initial application. Nav1.8-null mice also showed blunted pain and hyperalgesia to intracolonic mustard oil, which sensitizes nociceptors but also provokes tissue damage. To distinguish between a possible role for Nav1.8 in ongoing activity per se and ongoing activity after sensitization in the absence of additional stimuli, we tried a visceral model of tonic noxious chemical stimulation, cyclophosphamide cystitis. Cyclophosphamide produces cystitis by gradual accumulation of toxic metabolites in the bladder. In this model, Nav1.8-null mice showed normal responses. There were no differences between null mutants and their normal littermates in tissue damage and inflammation evoked by any of the stimuli tested, suggesting that the behavioral differences are not secondary to impairment of inflammatory responses. We conclude that there is an essential role for Nav1.8 in mediating spontaneous activity in sensitized nociceptors.