Effect of mexiletine on vincristine-induced painful neuropathy in mice.
In the present study, we examined the effect of mexiletine on vincristine-induced thermal hyperalgesia in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg one day after the measurement of the pre-drug latency in the tail-flick test, and then treated with a dose of 0.125 mg/kg twice a week for 6 weeks. In vincristine-treated mice, a significant decrease in tail-flick latency developed at 6 weeks after treatment. Pretreatment with mexiletine, at doses of 3, 10 and 30 mg/kg, i.p., dose-dependently increased the tail-flick latency in vincristine-treated mice. A significant reduction of the tail-flick latency was observed when the tail-flick latency was examined 60 min after i.t. administration of NG-nitro-L-arginine methyl ester (L-NAME, 30 nmol), a nitric oxide synthase (NOS) inhibitor, in naive mice. This L-NAME-induced thermal hyperalgesia was dose-dependently attenuated by pretreatment with mexiletine (10 and 30 mg/kg, i.p.), 10 min before the injection of L-NAME. The duration of nociceptive behavioral response induced by fenvalerate, at a dose of 0.1 microg, i.t., was significantly increased by pretreatment with L-NAME (30 nmol, i.t.). Intrathecal pretreatment with L-arginine (300 pmol) significantly reversed the L-NAME-induced enhancement of fenvalerate-induced nociceptive responses. The present study demonstrates that systemic mexiletine can effectively attenuate vincristine-induced thermal hyperalgesia. Furthermore, these results suggest that blockade of nitric oxide-induced enhancement of nociceptive transmission, in which tetrodotoxin-resistant sodium channels play an important role, may participate in the antinociceptive effect of mexiletine on vincristine-induced thermal hyperalgesia.
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo 142-8501, Japan. kamei@hoshi.ac.jp
Junzo
J
Kamei
Chihiro
C
Nozaki
Akiyoshi
A
Saitoh
D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D008801:Mexiletine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000633:toxicity; D009437:Neuralgia / Q000139:chemically induced / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage / Q000633:toxicity; D010147:Pain Measurement / Q000379:methods; D011722:Pyrethrins / Q000008:administration & dosage / Q000633:toxicity; D014750:Vincristine / Q000008:administration & dosage / Q000633:toxicity*
D004791:Enzyme Inhibitors; D009570:Nitriles; D011722:Pyrethrins; D008801:Mexiletine; D014750:Vincristine; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; C017690:fenvalerate