A Peripherally Acting Nav1.7 Sodium Channel Blocker Reverses Hyperalgesia and Allodynia on Rat Models of Inflammatory and Neuropathic Pain

• DOI: 10.1213/ane.0b013e3181b01b02
• Publication Date: 2009-08-15T07:14:22Z
• Authors: Erin McGowan; Scott B. Hoyt; Xiaohua Li; Kathryn A. Lyons; Catherine Abbadie
• Keywords: Mexiletine; Allodynia; Sodium channel blocker

Voltage-gated sodium channels (Na(v)1) are expressed in primary sensory neurons where they influence excitability via their role the generation and propagation of action potentials. Recently, human genetic data have shown that one channel subtype, Na(v)1.7, plays a major pain. We performed these studies to characterize antinociceptive effects N-[(R)-1-((R)-7-chloro-1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)-2-(2-fluorophenyl)-ethyl]-4-fluoro-2-trifluoromethyl-benzamide (BZP), non-central nervous system (CNS) penetrant small molecule with high affinity preferential selectivity for Na(v)1.7 over Na(v)1.8 Na(v)1.5.BZP was evaluated rat preclinical models inflammatory neuropathic pain compared standard analgesics. Two were used: complete Freund's adjuvant model spinal nerve ligation BZP also motor coordination assay assess its propensity CNS side effects.In chronic pain, displayed efficacy comparable leading In model, produced reversal hyperalgesia nonsteroidal antiinflammatory drugs, allodynia gabapentin mexiletine. Unlike compounds mexiletine, did not induce any impairment coordination.These suggest peripherally acting blocker, preferentially through could provide clinical relief without typical many existing treatments.