title: Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats.
abstract: M58373, 4-[2-(4-hydroxy-4-{[N-(4-isopropoxyphenyl)-N-methylamino]methyl}piperidin-1-yl)ethyl]benzonitrile monohydrochloride, is a novel compound, which has an inhibitory activity on neurotoxin binding to the site 2 of voltage-gated sodium channels. In this study, we investigated the effects of M58373 on substance P release from sensory neurons in vitro and pain behaviors/responses in rats, compared with mexiletine. M58373 (1-10 microM) inhibited veratridine-induced release of substance P from dorsal root ganglion cells. In the formalin test, oral M58373 (0.3-10 mg/kg) reduced the time spent in nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58373 (1-10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses in the uninjured paw. In contrast, oral mexiletine (10-100 mg/kg) had a narrow therapeutic dose range in both models because of the adverse effects on the central nervous system. These results suggest that M58373 is a favorable prototype for novel anti-neuropathic pain agents.
authors.affiliation: Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan. yakada@mochida.co.jp
authors.forename: Yasushige
authors.initials: Y
authors.lastname: Akada
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Amano
authors.forename: Yuka
authors.initials: Y
authors.lastname: Fukudome
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yamasaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Itoh
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yamamoto
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology / Q000517:prevention & control; D008297:Male; D008801:Mexiletine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000209:etiology / Q000517:prevention & control*; D009570:Nitriles / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013314:Stress, Mechanical; D013373:Substance P / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000700:Analgesics; C511970:M58373; D009570:Nitriles; D010880:Piperidines; D026941:Sodium Channel Blockers; D005557:Formaldehyde; D008801:Mexiletine; D013373:Substance P; D014701:Veratridine