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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.
AuthorsYasushige Akada, Shinichi Ogawa, Ken-ichi Amano, Yuka Fukudome, Fumiaki Yamasaki, Manabu Itoh, Ichiro Yamamoto
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 536 Issue 3 Pg. 248-55 (May 01 2006) ISSN: 0014-2999 [Print] Netherlands
PMID16603152 (Publication Type: Journal Article)
Chemical References
  • Analgesics
  • M58373
  • Nitriles
  • Piperidines
  • Sodium Channel Blockers
  • Formaldehyde
  • Mexiletine
  • Substance P
  • Veratridine
Topics
  • Analgesics (pharmacology)
  • Animals
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Formaldehyde
  • Ganglia, Spinal (cytology, drug effects, metabolism)
  • Hot Temperature
  • Hyperalgesia (etiology, prevention & control)
  • Male
  • Mexiletine (pharmacology)
  • Motor Activity (drug effects)
  • Neuralgia (etiology, prevention & control)
  • Nitriles (pharmacology)
  • Pain (chemically induced, prevention & control)
  • Pain Measurement (methods)
  • Piperidines (pharmacology)
  • Rats
  • Rats, Wistar
  • Sodium Channel Blockers (pharmacology)
  • Stress, Mechanical
  • Substance P (metabolism)
  • Veratridine (pharmacology)

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