RT Journal Article
SR Electronic
T1 Block of Peripheral Nerve Sodium Channels Selectively Inhibits Features of Neuropathic Pain in Rats
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 823
OP 832
DO 10.1124/mol.105.018127
VO 69
IS 3
A1 Richard M. Brochu
A1 Ivy E. Dick
A1 Jason W. Tarpley
A1 Erin McGowan
A1 David Gunner
A1 James Herrington
A1 Pengcheng P. Shao
A1 Dong Ok
A1 Chunshi Li
A1 William H. Parsons
A1 Gary L. Stump
A1 Christopher P. Regan
A1 Joseph J. Lynch, Jr.
A1 Kathryn A. Lyons
A1 Owen B. McManus
A1 Samantha Clark
A1 Zahid Ali
A1 Gregory J. Kaczorowski
A1 William J. Martin
A1 Birgit T. Priest
YR 2006
UL http://molpharm.aspetjournals.org/content/69/3/823.abstract
AB Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail to achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties of trans-N-{[2′-(aminosulfonyl)biphenyl-4-yl]methyl}-N-methyl-N′-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting sodium channel blocker. In whole-cell electrophysiological assays, CDA54 blocked the inactivated states of hNaV1.7 and hNaV1.8, two channels of the peripheral nervous system implicated in nociceptive transmission, with affinities of 0.25 and 0.18 μM, respectively. CDA54 displayed similar affinities for the tetrodotoxin-resistant Na+ current in small-diameter mouse dorsal root ganglion neurons. Peripheral nerve injury causes spontaneous electrical activity in normally silent sensory neurons. CDA54 inhibited these injury-induced spontaneous action potentials at concentrations 10-fold lower than those required to block normal A- and C-fiber conduction. Consistent with the selective inhibition of injury-induced firing, CDA54 (10 mg/kg p.o.) significantly reduced behavioral signs of neuropathic pain in two nerve injury models, whereas the same dose of CDA54 did not affect acute nociception or motor coordination. In anesthetized dogs, CDA54, at plasma concentrations of 6.7 μM, had no effect on cardiac electrophysiological parameters including conduction. Thus, the peripheral nerve sodium channel blocker CDA54 selectively inhibits sensory nerve signaling associated with neuropathic pain.