Envolvimento dos receptores de cininas e a sensibilização do canal TRPA1 em um modelo de neuropatia periférica induzida por cisplatina em camundongos

• Ano de defesa: 2024
• Autor(a) principal: Becker, Gabriela
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Santa Maria; Brasil; Bioquímica; UFSM; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica; Centro de Ciências Naturais e Exatas
• Palavras-chave em Português: Dor; Vias intracelulares; TRPs; Alodinia; Câncer; Pain; Intracellular pathways; CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA
• Link de acesso: http://repositorio.ufsm.br/handle/1/33450

Cisplatin, a widely used chemotherapy agent for the treatment of highly prevalent solid tumours, often has its therapeutic efficacy limited by severe neurotoxic effects, such as peripheral neuropathy. This condition poses substantial clinical challenges to patients undergoing cancer treatment, including the need for dose adjustments or even interruption of the therapeutic regimen. This scenario becomes even more complex with the difficulty in managing neuropathic patients since there is still a significant gap in the availability of effective drugs for controlling the symptoms of cisplatin-induced peripheral neuropathy. Therefore, it is essential to understand the pathophysiological mechanisms underlying these painful symptoms, aiming to develop more effective therapeutic approaches. In this context, kinin receptors, known for their fundamental role in developing chronic painful conditions, including those triggered by chemotherapy agents, emerge as targets of great interest for elucidation and possible therapeutic intervention. Thus, this study aimed to investigate the role of kinin receptors, B1 and B2, and the intracellular signalling pathways activated subsequent to the activation of these receptors in the sensitization of the TRPA1 channel in the context of cisplatin-induced peripheral neuropathy. The peripheral neuropathic pain model was induced with six intraperitoneal administrations of cisplatin (doses of 2.3 and 0.23 mg/kg) in male Swiss mice. Cisplatin caused pain symptoms (mechanical and cold allodynia), which were reduced by antagonists of kinin receptors B1 (DALBk) and B2 (Icatibant) or TRPA1 (A967079). In addition, antisense oligonucleotides for kinin receptors B1 and B2 reduced cisplatin-induced mechanical allodynia. Local subnociceptive doses of kinin B2 receptor (bradykinin) and TRPA1 channel (allyl isothiocyanate; AITC) agonists intensified the nociceptive behaviours elicited by cisplatin, an effect that was reduced by the administration of their respective antagonists. Using agonists and antagonists, we observed a possible interaction between the kinin B2 receptor and the TRPA1 channel in the painful behaviours associated with cisplatin-induced peripheral neuropathy. Finally, we demonstrated this interaction by observing that local administration of phospholipase C (PLC) and protein kinase C epsilon (PKCε) inhibitors significantly reduced the mechanical and cold hypersensitivity elicited by kinin B2 receptor and TRPA1 channel agonists in animals previously exposed to cisplatin. These findings highlight the crucial role of kinin receptors in cisplatin-induced peripheral neuropathy, especially in mechanical allodynia behaviour. Furthermore, we demonstrated that kinin B2 receptors interact with TRPA1 through PLC- and PKCε-mediated intracellular signalling. These results suggest that direct modulation of kinin receptors, or the intracellular signalling pathways underlying B2 receptor activation, may attenuate painful peripheral neuropathy associated with cisplatinbased cancer treatment, mitigating the impact on the quality of life of cancer patients and survivors who live with the painful symptoms caused by this chemotherapy agent.