Journal
PHARMACEUTICALS
Volume 16, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/ph16070959
Keywords
neuropathic pain; allodynia; chemotherapy; CIPN; bradykinin; protein kinase C & epsilon;
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Chemotherapy-induced peripheral neuropathy (CIPN), associated with cisplatin use, is a severe clinical problem. The activation of kinin B-2 receptors and sensitization of the TRPA1 channel are involved in cisplatin-induced peripheral neuropathy. However, the role of downstream signaling pathways in this model remains unknown.
Chemotherapy-induced peripheral neuropathy is a severe clinical problem frequently associated with cisplatin use. Although its pathophysiology is poorly understood, it is known that kinin receptors and the transient receptor potential ankyrin 1 (TRPA1) channel play a significant role in the peripheral neuropathy induced by cisplatin in rodents. However, the role of signalling pathways downstream from B-2 kinin receptors activation and sensitisation of the TRPA1 channel remains unknown in this model. The cisplatin-induced neuropathy model caused mechanical and cold allodynia in male Swiss mice. Antagonists for kinin B-2 and B-1 receptors and the TRPA1 channel attenuated the painful parameters. Local sub-nociceptive doses of kinin B-2 receptor (bradykinin) and TRPA1 channel (allyl isothiocyanate; AITC) agonists enhanced the painful parameters in cisplatin-treated mice, which their respective antagonists attenuated. Furthermore, we demonstrated the interaction between the kinin B-2 receptor and the TRPA1 channel in cisplatin-induced peripheral neuropathy since phospholipase C (PLC) and protein kinase C epsilon (PKCe) inhibitors attenuated the increase in mechanical and cold allodynia evoked by bradykinin and AITC in cisplatin-treated mice. Therefore, regulating the activation of signalling pathways downstream from the kinin B-2 receptors activation and TRPA1 channel sensitisation can mitigate the painful peripheral neuropathy decurrent of the oncology treatment with cisplatin.
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