Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.
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.
Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.
Gabriel S
GS
Bassi
Department of Pharmaceutical Sciences, Federal Rural University of Rio de Janeiro, BR 465/Km 07, 23890-000, Seropédica, RJ, Brazil.
David
D
do C Malvar
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.
Thiago M
TM
Cunha
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.
Fernando Q
FQ
Cunha
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil. alex_bioquimica@yahoo.com.br.
Alexandre
A
Kanashiro
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000523:psychology; D001522:Behavior, Animal; D016207:Cytokines / Q000378:metabolism; D058786:GABA-B Receptor Agonists / Q000008:administration & dosage; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007278:Injections, Spinal; D007719:Knee Joint / Q000276:immunology / Q000294:innervation*; D008297:Male; D008807:Mice, Inbred BALB C; D015213:Neuroimmunomodulation / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D015054:Zymosan; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D018080:Receptors, GABA-B; D015054:Zymosan; D048051:p38 Mitogen-Activated Protein Kinases
Arthritis; GABA-B receptor; Neuroimmunomodulation; Neutrophil; Sympathetic nervous system