Possible involvement of the spinal nitric oxide/cGMP pathway in vincristine-induced painful neuropathy in mice.
The mechanisms that underlie the development of vincristine-induced painful neuropathy are poorly understood. The nitric oxide (NO)-cGMP pathway has been reported to be involved in the spinal transmission of nociceptive information. In the present study, we examined whether alterations in spinal nociceptive processing via the NO-cGMP pathway contribute to vincristine-induced painful neuropathy in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg 1 day after the measurement of 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 latencies developed at 4 weeks after treatment. Pretreatment with L-arginine (30-300 mg/kg, s.c.), a substrate of NO synthase (NOS), dose-dependently increased the tail-flick latencies in vincristine-treated mice. The L-arginine-induced increase in tail-flick latencies in vincristine-treated mice was completely reversed by i.t. pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 3-30 nmol), a NOS inhibitor. Furthermore, i.t. pretreatment with 8-bromoguanosine 3', 5'-cyclic monophosphate (8-Br-cGMP, 0.3-3.0 nmol), a membrane-permeable cGMP analog, dose-dependently increased the tail-flick latencies in vincristine-treated mice. The contents of NO metabolites, cGMP and protein levels of neuronal NOS in the spinal cord in vincristine-treated mice were significantly reduced compared to those in vehicle-treated naive mice. These results indicate that dysfunction of the L-arginine/NO/cGMP cascade in the spinal cord may trigger vincristine-induced thermal hyperalgesia in mice.
Kamei
Junzo
J
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 4-41, Ebara 2-chome, Shinagawa-ku, Tokyo 142-8501, Japan. kamai@hoshi.ac.jp
Tamura
Naoya
N
Saitoh
Akiyoshi
A
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007278:Injections, Spinal / Q000379:methods; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement / Q000379:methods; D011810:Quinoxalines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*; D013997:Time Factors; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D014750:Vincristine; D001120:Arginine; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester