Blockade of bradykinin receptors or angiotensin II type 2 receptor prevents paclitaxel-associated acute pain syndrome in mice

TY - JOUR

T1 - Blockade of bradykinin receptors or angiotensin II type 2 receptor prevents paclitaxel-associated acute pain syndrome in mice

AU - Zanata, Graziele C.

AU - Pinto, Larissa G.

AU - da Silva, Nicole R.

AU - Lopes, Alexandre H.P.

AU - de Oliveira, Francisco F.B.

AU - Schivo, Ieda R.S.

AU - Cunha, Fernando Q.

AU - McNaughton, Peter

AU - Cunha, Thiago M.

AU - Silva, Rangel L.

N1 - Funding Information: The research leading to these results has received funding from the São Paulo Research Foundation (FAPESP) under grant 2013/08216‐2 (Center for Research in Inflammatory Disease‐CRID), from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), process number 401985/2017‐2 and from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES) number 1807866. FQC and TMC are recipients of the fellowship award from CNPq. LGP, FQC, PAM, and TMC are recipients of FAPESP/KCL Joint Grant, process number 2017/50419‐9. The authors are grateful to Atlante Silva Mendes for assistance in carrying out PCR and collecting samples. Funding Information: The research leading to these results has received funding from the S?o Paulo Research Foundation (FAPESP) under grant 2013/08216-2 (Center for Research in Inflammatory Disease-CRID), from the Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq), process number 401985/2017-2 and from Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - Brasil (CAPES) number 1807866. FQC and TMC are recipients of the fellowship award from CNPq. LGP, FQC, PAM, and TMC are recipients of FAPESP/KCL Joint Grant, process number 2017/50419-9. The authors are grateful to Atlante Silva Mendes for assistance in carrying out PCR and collecting samples. Publisher Copyright: © 2020 European Pain Federation - EFIC® Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/1

Y1 - 2021/1

N2 - Background: Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian, and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here, we assessed possible involvement of kinin–kallikrein and renin-angiotensin systems in P-APS in mice. Methods: Male mice C57Bl/6 wild type (WT) and knockouts for bradykinin receptors, B1 (B1−/−) and B2 (B2−/−), were used. Mechanical and cold allodynia were evaluated by using von Frey filaments and acetone test, respectively. P-APS was induced by administration of PCX 4 mg/kg, i.v. ACE inhibitors (captopril and enalapril), antagonists for angiotensin II type 1 (losartan) and type 2 ([AT2R]; PD123319 and EMA 401) receptors were administrated prior the treatment with PCX. RT-PCR was used to analyse the expression of mRNA for B1, B2 and AT2R receptors. Results: Administration of PCX in B1−/− and B2−/− mice induced lower mechanical and cold allodynia compared to the WT. However, the pre-treatment with ACE inhibitors reduced the development of mechanical and cold allodynia in P-APS. Surprisingly, we found that mice pre-treatment with the PD123319 or EMA401, but not losartan, prevented the development of mechanical and cold allodynia induced by PCX. Conclusion: Our results demonstrated the involvement of bradykinin receptors B1 and B2 as well as AT2R in the induction of P-APS in mice, and suggest the use of AT2R antagonists as a potential therapy for the prevention of P-APS in humans. Significance: Kinin–kallikrein and renin-angiotensin systems, through B1, B2 and AT2 receptors, potentiates paclitaxel-associated acute pain syndrome (P-APS) in mice. Antagonists for AT2R are potential alternatives to prevent P-APS.

AB - Background: Paclitaxel (PCX) is the first-line choice for the treatment of several types of cancer, including breast, ovarian, and lung cancers. However, patients who receive even a single dose with PCX commonly develop mechanical and cold allodynia, a symptom known as PCX-associated acute pain syndrome (P-APS). Here, we assessed possible involvement of kinin–kallikrein and renin-angiotensin systems in P-APS in mice. Methods: Male mice C57Bl/6 wild type (WT) and knockouts for bradykinin receptors, B1 (B1−/−) and B2 (B2−/−), were used. Mechanical and cold allodynia were evaluated by using von Frey filaments and acetone test, respectively. P-APS was induced by administration of PCX 4 mg/kg, i.v. ACE inhibitors (captopril and enalapril), antagonists for angiotensin II type 1 (losartan) and type 2 ([AT2R]; PD123319 and EMA 401) receptors were administrated prior the treatment with PCX. RT-PCR was used to analyse the expression of mRNA for B1, B2 and AT2R receptors. Results: Administration of PCX in B1−/− and B2−/− mice induced lower mechanical and cold allodynia compared to the WT. However, the pre-treatment with ACE inhibitors reduced the development of mechanical and cold allodynia in P-APS. Surprisingly, we found that mice pre-treatment with the PD123319 or EMA401, but not losartan, prevented the development of mechanical and cold allodynia induced by PCX. Conclusion: Our results demonstrated the involvement of bradykinin receptors B1 and B2 as well as AT2R in the induction of P-APS in mice, and suggest the use of AT2R antagonists as a potential therapy for the prevention of P-APS in humans. Significance: Kinin–kallikrein and renin-angiotensin systems, through B1, B2 and AT2 receptors, potentiates paclitaxel-associated acute pain syndrome (P-APS) in mice. Antagonists for AT2R are potential alternatives to prevent P-APS.

UR - http://www.scopus.com/inward/record.url?scp=85092107801&partnerID=8YFLogxK

U2 - 10.1002/ejp.1660

DO - 10.1002/ejp.1660

M3 - Article

C2 - 32965065

AN - SCOPUS:85092107801

SN - 1090-3801

VL - 25

SP - 189

EP - 198

JO - European Journal of Pain (United Kingdom)

JF - European Journal of Pain (United Kingdom)

IS - 1

ER -