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The Journal of Neuroscience, November 1, 2001, 21(21):8690-8696

The Involvement of the Tetrodotoxin-Resistant Sodium Channel Na_v1.8 (PN3/SNS) in a Rat Model of Visceral Pain

Naoki Yoshimura^{1, 2}, Satoshi Seki², Sanja D. Novakovic³, Elda Tzoumaka³, Vickie L. Erickson², Kristin A. Erickson², Michael B. Chancellor¹, and William C. de Groat²

Departments of ¹ Urology and ² Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, and ³ Neurobiology Unit, Roche Bioscience, Palo Alto, California 94304

The present study investigated the effect of inhibiting the expression of Na_v1.8 (PN3/SNS) sodium channels by an antisense oligodeoxynucleotide (ODN) on bladder nociceptive responses induced by intravesical acetic acid infusion in rats. Animals were injected intrathecally with either Na_v1.8 antisense or mismatch ODN. Control cystometrograms under urethane anesthesia during intravesical saline infusion exhibited intercontraction intervals (ICIs) that were significantly longer in antisense-treated rats than in mismatch ODN-treated rats. Intravesical infusion of 0.1% acetic acid induced bladder hyperactivity as reflected by a 68% reduction in ICIs in mismatch ODN-treated rats but did not significantly reduce ICIs in antisense-treated rats. The number of Fos-positive cells after acetic acid administration were significantly reduced in the L6 spinal cord from antisense-treated animals, compared with mismatch ODN-treated animals. In addition, Na_v1.8 immunoreactivity was reduced in L6 dorsal root ganglion neurons in the antisense-treated 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 bladder wall was also smaller in antisense-treated rats than in mismatch ODN-treated rats, whereas no changes were observed in TTX-sensitive currents. These results indicate that the Na_v1.8 TTX-resistant sodium channels are involved in the activation of afferent nerves after chemical irritation of the bladder. These channels represent a new target for the treatment of inflammatory pain from visceral organs such as the urinary bladder.

Key words: dorsal root ganglion; tetrodotoxin; Na_v1.8 sodium channels; urinary bladder; acetic acid; inflammation; antisense oligodeoxynucleotide

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21218690-07$05.00/0

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