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.
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Authors | Yasushige Akada, Shinichi Ogawa, Ken-ichi Amano, Yuka Fukudome, Fumiaki Yamasaki, Manabu Itoh, Ichiro Yamamoto |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 536
Issue 3
Pg. 248-55
(May 01 2006)
ISSN: 0014-2999 [Print] Netherlands |
PMID | 16603152
(Publication Type: Journal Article)
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Chemical References |
- Analgesics
- M58373
- Nitriles
- Piperidines
- Sodium Channel Blockers
- Formaldehyde
- Mexiletine
- Substance P
- Veratridine
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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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