PT  - JOURNAL ARTICLE
AU  - Steve McGaraughty
AU  - Katharine L. Chu
AU  - Marc J. C. Scanio
AU  - Michael E. Kort
AU  - Connie R. Faltynek
AU  - Michael F. Jarvis
TI  - A Selective Na<sub>v</sub>1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-<em>N</em>-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats
AID  - 10.1124/jpet.107.134148
DP  - 2008 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1204--1211
VI  - 324
IP  - 3
4099  - http://jpet.aspetjournals.org/content/324/3/1204.short
4100  - http://jpet.aspetjournals.org/content/324/3/1204.full
SO  - J Pharmacol Exp Ther2008 Mar 01; 324
AB  - We have recently reported that systemic delivery of A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], a selective Nav1.8 sodium channel blocker, reduces behavioral measures of chronic pain. In the current study, the effects of A-803467 on evoked and spontaneous firing of wide dynamic range (WDR) neurons were measured in uninjured and rats with spinal nerve ligations (SNLs). Administration of A-803467 (10–30 mg/kg i.v.) reduced mechanically evoked (10-g von Frey hair) and spontaneous WDR neuronal activity in SNL rats. In uninjured rats, A-803467 (20 mg/kg i.v.) transiently reduced evoked but not spontaneous firing of WDR neurons. The systemic effects of A-803467 in SNL rats were not altered by spinal transection or by systemic pretreatment with the transient receptor potential vanilloid type 1 (TRPV1) receptor agonist, resiniferatoxin, at doses that impair the function of TRPV1-expressing fibers. To determine sites of action, A-803467 was administered into spinal tissue, into the uninjured L4 dorsal root ganglion (DRG), or into the neuronal receptive field. Injections of A-803467 into the L4 DRG (30–100 nmol/1 μl) or into the hindpaw receptive field (300 nmol/50 μl) reduced evoked but not spontaneous WDR firing. In contrast, intraspinal (50–150 nmol/0.5 μl) injection of A-803467 decreased both evoked and spontaneous discharges of WDR neurons. Thus, Nav1.8 sodium channels on the cell bodies/axons within the L4 DRG as well as on peripheral and central terminals of primary afferent neurons regulate the inflow of low-intensity mechanical signals to spinal WDR neurons. However, Nav1.8 sodium channels on central terminals seem to be key to the modulation of spontaneous firing in SNL rats. The American Society for Pharmacology and Experimental Therapeutics