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 Na(v)1.8 (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(v)1.8 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(v)1.8 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(v)1.8 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.
Yoshimura
N
N
Departments of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. nyos@pitt.edu
Seki
S
S
Novakovic
S D
SD
Tzoumaka
E
E
Erickson
V L
VL
Erickson
K A
KA
Chancellor
M B
MB
de Groat
W C
WC
D019342:Acetic Acid; D000283:Administration, Intravesical; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D007278:Injections, Spinal; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013779:Tetrodotoxin / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D017833:Visceral Afferents / Q000187:drug effects / Q000378:metabolism
D062559:NAV1.8 Voltage-Gated Sodium Channel; D009479:Neuropeptides; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium; D019342:Acetic Acid