Abstract
Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.
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Acknowledgments
The research leading to these results received funding from the São Paulo Research Foundation (FAPESP, grants 2011/20343-4, 2011/19670-0, 2012/04237-2 and 2013/08216-2), from the National Council for Scientific and Technological Development (CNPq, grant 150718/2010-1, 478504/2010-1 and 142068/2012-8), from the European Union Seventh Framework Program [FP7-2007-2013] under grant agreement n° HEALTH-F4-2011-281608 (TIMER), and from the University of São Paulo NAP-DIN (grant 11.1.21625.01.0). The authors thank Ieda R. Santos, Sérgio R. Rosa, and Giuliana Bertozi for technical assistance.
Author contributions
G.S.B. and A.K. designed the study. G.S.B. and A.K. performed the mouse experiments. A.K. wrote the manuscript. G.S.B, D.M., T.M.C, and F.Q.C. reviewed the manuscript.
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All the experiments were conducted following the National Institute of Health guidelines for the welfare of experimental animals after approval by the Ethics Committee of the Ribeirão Preto Medical School (COBEA Protocol 137/2013).
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Bassi, G.S., do C. Malvar, D., Cunha, T.M. et al. Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis. Naunyn-Schmiedeberg's Arch Pharmacol 389, 851–861 (2016). https://doi.org/10.1007/s00210-016-1248-0
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DOI: https://doi.org/10.1007/s00210-016-1248-0