Anti-allodynic effect of NW-1029, a novel Na+ channel blocker, in experimental animal models of inflammatory and neuropathic pain

Abstract

NW-1029, a benzylamino propanamide derivative, was selected among several molecules of this chemical class on the basis of its affinity for the [(3)H]batracotoxin ligand displacement of the Na(+) channel complex and also on the basis of its voltage and use-dependent inhibitory action on the Na(+) currents of the rat DRG (dorsal root ganglia) sensory neuron. This study evaluated the analgesic activity of NW-1029 in animal models of inflammatory and neuropathic pain (formalin test in mice, complete Freund's adjuvant and chronic constriction injury in rats) as well as in acute pain test (hot-plate and tail-flick in rats). Orally administered NW-1029 dose-dependently reduced cumulative licking time in the early and late phase of the formalin test (ED(50)=10.1 mg/kg in the late phase). In the CFA model, NW-1029 reversed mechanical allodynia (von Frey test) after both i.p. and p.o. administration (ED(50)=0.57 and 0.53 mg/kg), respectively. Similarly, NW-1029 reversed mechanical allodynia in the CCI model after both i.p. and p.o. administration yielding an ED(50) of 0.89 and 0.67 mg/kg, respectively. No effects were observed in the hot-plate and tail-flick tests up to 30 mg/kg p.o. The compound orally administered (0.1-10 mg/kg) was well tolerated, without signs of neurological impairment up to high doses (ED(50)=470 and 245 mg/kg in rat and mice Rotarod test, respectively). These results indicate that NW-1029 has anti-nociceptive properties in models of inflammatory and neuropathic pain.

Topisches Ambroxol zur Behandlung neuropathischer Schmerzen

“…Die Na v 1.8-Blockade, z. B. durch Ambroxol, wird letzlich auch deshalb als Option zur Behandlung neuropathischer Schmerzen betrachtet, weil Untersuchungen mit Na v 1.8-freien Mäusen und Na v 1.8-blockierenden Substanzen eine geringere mechanische, thermische und viszerale Übererregbarkeit im Tiermodel belegen [1,4,11,18,20,21,45,46].…”

The use of the antimicrobial peptide piscidin (PCD)-1 as a novel anti-nociceptive agent

“…The detailed mechanisms of neuropathic pain remain unclear. Neuropathic pain is a widespread health problem associated with nerve injury, prolonged tissue damage, or injury to the peripheral or central nervous system (CNS); the resulting pain is the result of complex changes occurring at various levels in nociceptive pathways [19]. Patients with neuropathic pain often develop hyperalgesia (an increased response to painful stimuli), allodynia (pain evoked by non-painful stimuli), and spontaneous pain and resistance to opioids and other analgesics, including non-steroidal anti-inflammatory drugs [20e24].…”

A Selective Nav1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats

“…Further validation of the Na v 1.8 role in neuropathic pain was generated from studies using antisense oligodeoxynucleotides, showing clear attenuation of hyperalgesia and allodynia in nerve-injured animals (Porreca et al, 1999;Lai et al, 2002;Joshi et al, 2006). Furthermore, systemic or spinal delivery of nonselective and preferential Na v 1.8 channel blockers also reduced hyperalgesia and allodynia in animal models of pathological pain (Veneroni et al, 2003;Gaida et al, 2005;Akada et al, 2006;Brochu et al, 2006;Ekberg et al, 2006).…”