title: Potentiation of Paclitaxel-Induced Pain Syndrome in Mice by Angiotensin I Converting Enzyme Inhibition and Involvement of Kinins.
abstract: Paclitaxel is a chemotherapeutic agent used to treat solid tumours. However, it causes an acute and neuropathic pain syndrome that limits its use. Among the mechanisms involved in neuropathic pain caused by paclitaxel is activation of kinin receptors. Angiotensin converting enzyme (ACE) inhibitors can enhance kinin receptor signalling. The goal of this study was to evaluate the role of kinins on paclitaxel-associated acute pain syndromes (P-APS) and the effect of ACE inhibition on P-APS and paclitaxel-associated chronic peripheral neuropathy (P-CPN) in mice. Herein, we show that paclitaxel caused mechanical allodynia and spontaneous nociceptive behaviour that was reduced by antagonists of kinin receptors B1(DALBk and SSR240612) and B2(Hoe140 and FR173657). Moreover, enalapril (an ACE inhibitor) enhanced the mechanical allodynia induced by a low dose of paclitaxel. Likewise, paclitaxel injection inhibited ACE activity and increased the expressions of B1and B2receptors and bradykinin-related peptides levels in peripheral tissue. Together, our data support the involvement of kinin receptors in the P-APS and suggest kinin receptor antagonists to treat this syndrome. Because hypertension is the most frequent comorbidity affecting cancer patients, treatment of hypertension with ACE inhibitors in patients undergoing paclitaxel chemotherapy should be reviewed, since this could enhance the P-APS and P-CPN.
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.
authors.forename: Indiara
authors.initials: I
authors.lastname: Brusco
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.|Institute of Genetics and Biochemestry, Federal University of Uberlandia, Uberlandia, MG, Brazil.
authors.forename: Cássia Regina
authors.initials: CR
authors.lastname: Silva
authors.affiliation: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Trevisan
authors.affiliation: Graduate Program in Biochemistry and Molecular Pharmacology, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Graduate Program in Medicine and Biomedicine-Institute of Education and Research Santa Casa, Belo Horizonte, MG, Brazil.
authors.forename: Camila
authors.initials: C
authors.lastname: de Campos Velho Gewehr
authors.affiliation: Graduate Program in Biochemistry and Molecular Pharmacology, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Graduate Program in Medicine and Biomedicine-Institute of Education and Research Santa Casa, Belo Horizonte, MG, Brazil.
authors.forename: Flávia Karine
authors.initials: FK
authors.lastname: Rigo
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.
authors.forename: Lidia
authors.initials: L
authors.lastname: La Rocca Tamiozzo
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.
authors.forename: Mateus Fortes
authors.initials: MF
authors.lastname: Rossato
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.|Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Raquel
authors.initials: R
authors.lastname: Tonello
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.
authors.forename: Gerusa Duarte
authors.initials: GD
authors.lastname: Dalmolin
authors.affiliation: Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil.
authors.forename: Daniela
authors.initials: D
authors.lastname: de Almeida Cabrini
authors.affiliation: Graduate Program in Biochemistry and Molecular Pharmacology, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.|Graduate Program in Medicine and Biomedicine-Institute of Education and Research Santa Casa, Belo Horizonte, MG, Brazil.
authors.forename: Marcus Vinícius
authors.initials: MV
authors.lastname: Gomez
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil.|Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.|Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Juliano
authors.initials: J
authors.lastname: Ferreira
authors.affiliation: Graduate Program in Biological Sciences: Biochemistry Toxicology, Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Av. Roraima 1000, Camobi, Santa Maria, RS, 97105-900, Brazil. saramarchesan@hotmail.com.
authors.forename: Sara Marchesan
authors.initials: SM
authors.lastname: Oliveira
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001920:Bradykinin / Q000378:metabolism*; D004357:Drug Synergism; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism*; D017239:Paclitaxel / Q000633:toxicity*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D018002:Receptors, Bradykinin / Q000378:metabolism*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000970:Antineoplastic Agents; D018002:Receptors, Bradykinin; D017239:Paclitaxel; D001920:Bradykinin
keywords: Bradykinin; Chemotherapy; Mechanical allodynia; Neuropathy; Nociceptive behaviour