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Published online before print January 18, 2008

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(Journal of Leukocyte Biology. 2008;83:824-832.)
© 2008 by Society for Leukocyte Biology

Crucial role of neutrophils in the development of mechanical inflammatory hypernociception

Thiago M. Cunha^*, Waldiceu A. Verri, Jr.^*, Ieda R. Schivo^*, Marcelo H. Napimoga, Carlos A. Parada^*, Stephen Poole, Mauro M. Teixeira, Sergio H. Ferreira^* and Fernando Q. Cunha^*,1

^* Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, Ribeirão Preto, SP, Brazil;
Laboratory of Molecular Biology, University of Uberaba, Uberaba, Brazil;
Division of Immunology and Endocrinology, National Institute for Biological Standards and Control, Potters Bar, United Kingdom; and
Departamento de Bioquímica e Imunologia, Instituto Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

¹ Correspondence: Faculdade de Medicina de Ribeirão Preto, USP, Avenida Bandeirantes, 3900, 14049-900, Ribeirão Preto, SP, Brazil. E-mail: fdqcunha{at}fmrp.usp.br

ABSTRACT

Neutrophil migration is responsible for tissue damage observed in inflammatory diseases. Neutrophils are also implicated in inflammatory nociception, but mechanisms of their participation have not been elucidated. In the present study, we addressed these mechanisms in the carrageenan-induced mechanical hypernociception, which was determined using a modification of the Randall-Sellito test in rats. Neutrophil accumulation into the plantar tissue was determined by the contents of myeloperoxidase activity, whereas cytokines and PGE₂ levels were measured by ELISA and radioimmunoassay, respectively. The pretreatment of rats with fucoidin (a leukocyte adhesion inhibitor) inhibited carrageenan-induced hypernociception in a dose- and time-dependent manner. Inhibition of hypernociception by fucoidin was associated with prevention of neutrophil recruitment, as it did not inhibit the hypernociception induced by the direct-acting hypernociceptive mediators, PGE₂ and dopamine, which cause hypernociception, independent of neutrophils. Fucoidin had no effect on carrageenan-induced TNF-, IL-1β, and cytokine-induced neutrophil chemoattractant 1 (CINC-1)/CXCL1 production, suggesting that neutrophils were not the source of hypernociceptive cytokines. Conversely, hypernociception and neutrophil migration induced by TNF-, IL-1β, and CINC-1/CXCL1 was inhibited by fucoidin, suggesting that neutrophils are involved in the production of direct-acting hypernociceptive mediators. Indeed, neutrophils stimulated in vitro with IL-1β produced PGE₂, and IL-1β-induced PGE₂ production in the rat paw was inhibited by the pretreatment with fucoidin. In conclusion, during the inflammatory process, the migrating neutrophils participate in the cascade of events leading to mechanical hypernociception, at least by mediating the release of direct-acting hypernociceptive mediators, such as PGE₂. Therefore, the blockade of neutrophil migration could be a target to development of new analgesic drugs.

Key Words: hyperalgesia • pain • nociception • cytokines • PGE₂