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Endothelin receptor type A is involved in the development of oxaliplatin-induced mechanical allodynia and cold allodynia acting through spinal and peripheral mechanisms in rats.

ABSTRACT: Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes severe neuropathic pain typically encompassing cold allodynia and long-lasting mechanical allodynia. Endothelin has been shown to modulate nociceptive transmission in a variety of pain disorders. However, the action of endothelin varies greatly depending on many variables, including pain causes, receptor types (endothelin type A (ET_A) and B (ET_B) receptors) and organs (periphery and spinal cord). Therefore, in this study, we investigated the role of endothelin in a Sprague-Dawley rat model of oxaliplatin-induced neuropathic pain. Intraperitoneal administration of bosentan, a dual ET_A/ET_B receptor antagonist, effectively blocked the development or prevented the onset of both cold allodynia and mechanical allodynia. The preventive effects were exclusively mediated by ET_A receptor antagonism. Intrathecal administration of an ET_A receptor antagonist prevented development of long-lasting mechanical allodynia but not cold allodynia. In marked contrast, an intraplantar ET_A receptor antagonist had a suppressive effect on cold allodynia but only had a partial and transient effect on mechanical allodynia. In conclusion, ET_A receptor antagonism effectively prevented long-lasting mechanical allodynia through spinal and peripheral actions, while cold allodynia was prevented through peripheral actions.

SUBMITTER: Matsuura K

PROVIDER: S-EPMC8679041 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

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