The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain

The present study investigated the effect of inhibiting the expression of N a(v)1.8 (PN3/SNS) sodium channels by an antisense oligodeoxynucleotide (ODN ) on bladder nociceptive responses induced by intravesical acetic acid infu sion in rats. Animals were injected intrathecally with either Na(v)1.8 anti sense or mismatch ODN. Control cystometrograms under urethane anesthesia du ring intravesical saline infusion exhibited intercontraction intervals (ICI s) that were significantly longer in antisense-treated rats than in mismatc h ODN-treated rats. Intravesical infusion of 0.1% acetic acid induced bladd er hyperactivity as reflected by a 68% reduction in ICIs in mismatch ODN-tr eated rats but did not significantly reduce ICIs in antisense-treated rats. The number of Fos-positive cells after acetic acid administration were sig nificantly reduced in the L6 spinal cord from antisense-treated animals, co mpared with mismatch ODN-treated animals. In addition, Na(v)1.8 immunoreact ivity was reduced in L6 dorsal root ganglion neurons in the antisense-treat ed rat. In patch-clamp recordings, the conductance density of TTX-resistant sodium currents in dissociated bladder afferent neurons that were labeled by axonal transport of a fluorescent dye, Fast Blue, injected into the blad der wall was also smaller in antisense-treated rats than in mismatch ODN-tr eated rats, whereas no changes were observed in TTX-sensitive currents. The se results indicate that the Na(v)1.8 TTX-resistant sodium channels are inv olved in the activation of afferent nerves after chemical irritation of the bladder. These channels represent a new target for the treatment of inflam matory pain from visceral organs such as the urinary bladder.