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Kinin Receptors Sensitize TRPV4 Channel and Induce Mechanical Hyperalgesia: Relevance to Paclitaxel-Induced Peripheral Neuropathy in Mice

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Abstract

Kinin B1 (B1R) and B2 receptors (B2R) and the transient receptor potential vanilloid 4 (TRPV4) channel are known to play a critical role in the peripheral neuropathy induced by paclitaxel (PTX) in rodents. However, the downstream pathways activated by kinin receptors as well as the sensitizers of the TRPV4 channel involved in this process remain unknown. Herein, we investigated whether kinins sensitize TRPV4 channels in order to maintain PTX-induced peripheral neuropathy in mice. The mechanical hyperalgesia induced by bradykinin (BK, a B2R agonist) or des-Arg9-BK (DABK, a B1R agonist) was inhibited by the selective TRPV4 antagonist HC-067047. Additionally, BK was able to sensitize TRPV4, thus contributing to mechanical hyperalgesia. This response was dependent on phospholipase C/protein kinase C (PKC) activation. The selective kinin B1R (des-Arg9-[Leu8]-bradykinin) and B2R (HOE 140) antagonists reduced the mechanical hyperalgesia induced by PTX, with efficacies and time response profiles similar to those observed for the TRPV4 antagonist (HC-067047). Additionally, both kinin receptor antagonists inhibited the overt nociception induced by hypotonic solution in PTX-injected animals. The same animals presented lower PKCε levels in skin and dorsal root ganglion samples. The selective PKCε inhibitor (εV1–2) reduced the hypotonicity-induced overt nociception in PTX-treated mice with the same magnitude observed for the kinin receptor antagonists. These findings suggest that B1R or B2R agonists sensitize TRPV4 channels to induce mechanical hyperalgesia in mice. This mechanism of interaction may contribute to PTX-induced peripheral neuropathy through the activation of PKCε. We suggest these targets represent new opportunities for the development of effective analgesics to treat chronic pain.

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Acknowledgments

The study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC) e Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA). M.A.B and M.N.M. are PhD students funded by the CNPq. G.C.S. and F.C.D are master’s students funded by the CAPES.

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  1. João B. Calixto

    Present address: Centro de Inovação e Ensaios Pré-clínicos (CIEnP), Av. Luiz Bouteux Piazza, 1302, Cachoeira do Bom Jesus, Florianópolis, SC, 88056-000, Brazil

Authors and Affiliations

  1. Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Florianópolis, SC, 88049-900, Brazil

    Robson Costa, Maíra A. Bicca, Marianne N. Manjavachi, Gabriela C. Segat & João B. Calixto

  2. Programa de Pós-graduação de Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, RJ, Brazil

    Robson Costa & Fabiana Chaves Dias

  3. Programa de Pós-Graduação em Biologia Parasitária, Universidade Ceuma, São Luís, MA, Brazil

    Elizabeth S. Fernandes

  4. Vascular Biology and Inflammation Section, Cardiovascular Division, King’s College London, London, UK

    Elizabeth S. Fernandes

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  1. Robson Costa
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Costa, R., Bicca, M.A., Manjavachi, M.N. et al. Kinin Receptors Sensitize TRPV4 Channel and Induce Mechanical Hyperalgesia: Relevance to Paclitaxel-Induced Peripheral Neuropathy in Mice. Mol Neurobiol 55, 2150–2161 (2018). https://doi.org/10.1007/s12035-017-0475-9

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