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

• Published in: European journal of pain 2021-01, Vol.25 (1), p.189-198
• Main Authors: Zanata, Graziele C., Pinto, Larissa G., Silva, Nicole R., Lopes, Alexandre H. P., Oliveira, Francisco F. B., Schivo, Ieda R. S., Cunha, Fernando Q., McNaughton, Peter, Cunha, Thiago M., Silva, Rangel L.
• Format: Article
• Language: English
• Subjects: Acute Pain; Angiotensin II Type 2 Receptor Blockers; Animals; Bradykinin; Bradykinin Receptor Antagonists; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Paclitaxel - toxicity; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2 - genetics; Receptors, Bradykinin
• ISSN: 1090-3801; 1532-2149
• DOI: 10.1002/ejp.1660

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.