Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia in rats

<p>Background: Oxaliplatin, a chemotherapy medication, causes severe peripheral neuropathy. Although oxaliplatin-induced peripheral neuropathy is a dose-limiting toxicity, a therapeutic strategy against its effects has not been established. We previously reported the involvement of N-methyl-D-aspartate receptors and their intracellular signalling pathway in oxaliplatin-induced mechanical allodynia in rats. The aim of this study was to clarify the involvement of spinal glutamate transmission in oxaliplatin-induced mechanical allodynia. </p><p>Methods: Male Sprague-Dawley rats aged 6 weeks were used for the oxaliplatin-induced mechanical allodynia. Male BALB/c mice aged 7-8 weeks were used for the in vivo tumor growth model. To establish the oxaliplatin-induced mechanical allodynia, oxaliplatin (4 mg/kg, i.p.) was administered twice a week for 4 weeks. Riluzole (12 mg/kg, p.o.) was administered once a day for 27 days from day 1. Mechanical allodynia was assessed by the von Frey test. Rota-rod test was performed to assess motor coordination. We carried out in vivo spinal microdialysis. After 15 min of the start of dialysates collection, each rat was placed in an acrylic box with a polypropylene-brush floor for 5 min.</p><p>Results: In vivo spinal microdialysis, the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation markedly increased extracellular glutamate concentration. In these rats, the expression of glutamate transporter 1 (GLT-1), which plays a major role in glutamate uptake, was decreased in the spinal cord. Co-administration of riluzole, which inhibits glutamate release, prevented the decrease in the paw withdrawal threshold in oxaliplatin-treated rats. Conversely, riluzole did not affect motor coordination. In vivo spinal microdialysis showed that repeated administration of riluzole suppressed the oxaliplatin-induced increase of basal glutamate concentration and enhancement of glutamate release induced by mechanical stimulation. Riluzole also suppressed the decrease of GLT-1 expression. In addition, riluzole had no effect on the oxaliplatin-induced cytotoxicity in cultured murine colon adenocarcinoma 26 (C-26) cells or inhibition of tumor growth in tumor cells-implanted mice.</p><p>Conclusions: These results suggest that spinal glutamate transmission plays an important role in the development of oxaliplatin-induced mechanical allodynia, and support for the potency of riluzole as a prophylaxis for oxaliplatin-induced mechanical allodynia.</p>