Published online before print October 3, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0207123

Received for publication February 23, 2007.
Revised August 31, 2007.
Accepted for publication September 1, 2007.

Article

Involvement of LTB₄ in zymosan-induced joint nociception in mice: participation of neutrophils and PGE₂

Ana T. G. Guerrero ^*, Waldiceu A. Verri Jr.^*, Thiago M. Cunha ^*, Tarcilia A. Silva , Ieda R. S. Schivo ^*, Daniela Dal-Secco ^*, Claudio Canetti , Francisco A. C. Rocha , Carlos A. Parada ^*, Fernando Q. Cunha ^*@, and Sérgio H. Ferreira ^*

*Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil; Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, Minas Gerais, Brazil; Departament of Internal Medicine, School of Medicine, Federal University of Ceara, Fortaleza-CE, Brazil; and Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

^@ To whom correspondence should be addressed. E-mail: fdqcunha{at}fmrp.usp.br.

Abstract

Leukotriene B₄ (LTB₄) mediates different inflammatory events such as neutrophil migration and pain. The present study addressed the mechanisms of LTB₄-mediated joint inflammation-induced hypernociception. It was observed that zymosan-induced articular hypernociception and neutrophil migration were reduced dose-dependently by the pretreatment with MK886 (1–9 mg/kg; LT synthesis inhibitor) as well as in 5-lypoxygenase-deficient mice (5LO^-/-) or by the selective antagonist of the LTB₄ receptor (CP105696; 3 mg/kg). Histological analysis showed reduced zymosan-induced articular inflammatory damage in 5LO^-/- mice. The hypernociceptive role of LTB₄ was confirmed further by the demonstration that joint injection of LTB₄ induces a dose (8.3, 25, and 75 ng)-dependent articular hypernociception. Furthermore, zymosan induced an increase in joint LTB₄ production. Investigating the mechanism underlying LTB₄ mediation of zymosan-induced hypernociception, LTB₄-induced hypernociception was reduced by indomethacin (5 mg/kg), MK886 (3 mg/kg), celecoxib (10 mg/kg), antineutrophil antibody (100 µg, two doses), and fucoidan (20 mg/kg) treatments as well as in 5LO^-/- mice. The production of LTB₄ induced by zymosan in the joint was reduced by the pretreatment with fucoidan or antineutrophil antibody as well as the production of PGE₂ induced by LTB₄. Therefore, besides reinforcing the role of endogenous LTB₄ as an important mediator of inflamed joint hypernociception, these results also suggested that the mechanism of LTB₄-induced articular hypernociception depends on prostanoid and neutrophil recruitment. Furthermore, the results also demonstrated clearly that LTB₄-induced hypernociception depends on the additional release of endogenous LTs. Concluding, targeting LTB₄ synthesis/action might constitute useful therapeutic approaches to inhibit articular inflammatory hypernociception.

Key Words: joint pain • arthritis • hyperalgesia • 5-lypoxygenase • hypernociception

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