Deficits in Visceral Pain and Referred Hyperalgesia in Nav1.8 (SNS/PN3)-Null Mice

Abstract

The tetrodotoxin-resistant sodium channel alpha 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.

Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function

“…Increased sensitivity to somatic stimuli, in the form of referred hyperalgesia and tactile allodynia, has been noted in the presence of visceral inflammation (34,53,54,90). In separate groups of mice, we evaluated mechanical somatic sensitivity using a calibrated series of von Frey hairs on the plantar region of the hindpaw and the pelvic region overlying the urinary bladder in NGF-OE transgenic mice and WT littermate controls.…”

“…Referred (secondary) hyperalgesia and tactile allodynia were measured using calibrated von Frey hairs with forces of 0.04, 0.16, 0.4, 1, and 4 g applied to the abdomen (53,54,90) and hindpaw (11,34,90). Mice were tested in individual Plexiglas chambers with a stainless-steel wire grid floor.…”

Measurement of Tactile Allodynia in a Murine Model of Bacterial Prostatitis

“…Referred hyperalgesia and tactile allodynia was tested using von Frey filaments applied to the abdomen 11,12 and the plantar region of the hind paw 13 .…”

Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders

“…To assess the role of Na v 1.7 further, especially in relation to other sodium channels expressed in peripheral sensory neurons, the same researchers created mice deficient in both Na v 1.7 and Na v 1.8 (27). Mice deficient in Na v 1.8 had deficits in sensing inflammatory pain (initiated by tissue damage/inflammation) and visceral pain (initiated by damage or injury to internal organs) but not neuropathic pain (28). The thermal pain threshold in mice deficient in both Na v 1.7 and Na v 1.8 mice was twice that of mice lacking only Na v 1.7.…”