Excessive spinal glutamate transmission is involved in oxaliplatin-induced mechanical allodynia: a possibility for riluzole as a prophylactic drug

Shota Yamamoto,Ken Masuguchi,Satohiro Masuda,Nana Ozawa,Yuko Ono,Hitomi Higuchi,Nobuaki Egashira,Shohei Mitsuyasu,Takehiro Kawashiri,Soichiro Ushio

doi:10.1038/s41598-017-08891-1

Shota Yamamoto, Ken Masuguchi + Show 8 more

Open Access

https://doi.org/10.1038/s41598-017-08891-1

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Journal: Scientific Reports	Publication Date: Aug 29, 2017
Citations: 33	License type: open-access

Affiliation: Kyushu University, Kyushu University Hospital

Abstract

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. In vivo spinal microdialysis revealed that the baseline glutamate concentration was elevated in oxaliplatin-treated rats, and that mechanical stimulation of the hind paw markedly increased extracellular glutamate concentration in the same rats. 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. Moreover, we explored the potential of pharmacological therapy targeting maintenance of extracellular glutamate homeostasis. The administration of riluzole, an approved drug for amyotrophic lateral sclerosis, suppressed the increase of glutamate concentration, the decrease of GLT-1 expression and the development of mechanical allodynia. These results suggest that oxaliplatin disrupts the extracellular glutamate homeostasis in the spinal cord, which may result in neuropathic symptoms, and support the use of riluzole for prophylaxis of oxaliplatin-induced mechanical allodynia.

Highlights

Oxaliplatin has widely been used for the treatment of solid cancers such as colorectal cancer and gastric cancer
Using low-invasive in vivo spinal microdialysis, we evaluated the glutamate concentration in the cerebrospinal fluid of the lumbar spinal cord (L4–L6)
These results suggest that oxaliplatin treatment changes the reactivity to mechanical stimulation to enhance the increase in glutamate concentration, which is capable of inducing mechanical allodynia

Summary

Introduction

Oxaliplatin has widely been used for the treatment of solid cancers such as colorectal cancer and gastric cancer Excessive activation of glutamate receptors, in particular N-methyl-D-aspartate receptors (NMDAR), in the spinal cord is a hallmark mechanism of neuropathic pain[5,6,7]. We have previously reported that repeated administration of oxaliplatin induced cold allodynia in the early phase and mechanical allodynia in the late phase in rats[18]. We have reported that Ca2+ channels/nuclear factor of activated T-cell/transient receptor potential melastatin 8 pathway is involved in the oxaliplatin-induced cold allodynia[20]. We have shown that the NMDAR-Ca2+/calmodulin-dependent protein kinase II pathway is involved in oxaliplatin-induced mechanical allodynia[22]. Whether oxaliplatin induces an abnormality of extracellular glutamate concentration in the spinal cord remains unclear

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