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NEUROPHARMACOLOGY

A Selective Na_v1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

We have recently reported that systemic delivery of A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], a selective Na_v1.8 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, Na_v1.8 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, Na_v1.8 sodium channels on central terminals seem to be key to the modulation of spontaneous firing in SNL rats.

Address correspondence to: Dr. Steve McGaraughty, Neuroscience Research, Abbott Laboratories, R4PM, AP9–1, 100 Abbott Park Rd., Abbott Park, IL 60064-6118. E-mail: Steve.P.McGaraughty{at}abbott.com