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Bradykinin Receptors Play a Critical Role in the Chronic Post-ischaemia Pain Model

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Abstract

Complex regional pain syndrome type-I (CRPS-I) is a chronic painful condition resulting from trauma. Bradykinin (BK) is an important inflammatory mediator required in acute and chronic pain response. The objective of this study was to evaluate the association between BK receptors (B1 and B2) and chronic post-ischaemia pain (CPIP) development in mice, a widely accepted CRPS-I model. We assessed mechanical and cold allodynia, and paw oedema in male and female Swiss mice exposed to the CPIP model. Upon induction, the animals were treated with BKR antagonists (HOE-140 and DALBK); BKR agonists (Tyr-BK and DABK); antisense oligonucleotides targeting B1 and B2 and captopril by different routes in the model (7, 14 and 21 days post-induction). Here, we demonstrated that treatment with BKR antagonists, by intraperitoneal (i.p.), intraplantar (i.pl.), and intrathecal (i.t.) routes, mitigated CPIP-induced mechanical allodynia and oedematogenic response, but not cold allodynia. On the other hand, i.pl. administration of BKR agonists exacerbated pain response. Moreover, a single treatment with captopril significantly reversed the anti-allodynic effect of BKR antagonists. In turn, the inhibition of BKRs gene expression in the spinal cord inhibited the nociceptive behaviour in the 14th post-induction. The results of the present study suggest the participation of BKRs in the development and maintenance of chronic pain associated with the CPIP model, possibly linking them to CRPS-I pathogenesis.

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Acknowledgements

We thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC), INCT-INOVAMED Program (Grant 465430/2014-7), and Programa de Pós-Graduação em Neurociências (PGN), all from Brazil, supported this work. E.C.D.G. is a Ph.D. student in neuroscience receiving grants from FAPESC. S.M.O., J.B.C., A.R.S.S., and R.C.D are the recipient of a research productivity fellowship from the CNPq.

Funding

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC), INCT-INOVAMED Program (Grant Number 465430/2014-7), and Programa de Pós-Graduação em Neurociências (PGN).

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Authors and Affiliations

  1. Laboratory of Autoimmunity and Immunopharmacology, Department of Health Sciences, Campus Araranguá, Federal University of Santa Catarina, Araranguá, SC, 88906-072, Brazil

    Elaine C. D. Gonçalves, Graziela Vieira, Tainara R. Gonçalves, Maíra Cola & Rafael C. Dutra

  2. Post-Graduate Program of Neuroscience, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Elaine C. D. Gonçalves & Rafael C. Dutra

  3. Laboratory of Neurobiology of Pain and Inflammation, Department of Physiological Sciences, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Róli R. Simões & Adair R. S. Santos

  4. Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, 97105-900, Brazil

    Indiara Brusco & Sara M. Oliveira

  5. Center of Innovation and Preclinical Research, Florianópolis, SC, 88056-000, Brazil

    João B. Calixto

  6. Laboratório de Autoimunidade e Imunofarmacologia (LAIF), Departamento de Ciências da Saúde, Universidade Federal de Santa Catarina, Campus Araranguá. Rodovia Jorge Lacerda, Km 35.4 – Jardim das Avenidas, Araranguá, SC, CEP 88906-072, Brazil

    Rafael C. Dutra

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  1. Elaine C. D. Gonçalves
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Contributions

ECDG designed and performed experiments, wrote the manuscript and supervised the project. GV, TRG, RRS, IB, and SMO performed experiments and analysed data. JBC, MC and ARSS wrote the manuscript. RCD supervised the project, wrote and refined the manuscript.

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Correspondence to Rafael C. Dutra.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the Ethics Committee of Universidade Federal de Santa Catarina (CEUA-UFSC, Protocol Number PP00956/2014).

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Gonçalves, E.C.D., Vieira, G., Gonçalves, T.R. et al. Bradykinin Receptors Play a Critical Role in the Chronic Post-ischaemia Pain Model. Cell Mol Neurobiol 41, 63–78 (2021). https://doi.org/10.1007/s10571-020-00832-3

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