ABSTRACT
The gamma amino butyric acid B (GABA(B)) receptor is a G protein-coupled receptor (GPCR) involved in synaptic transmission. Recent data indicate it to be also expressed on immune cells, along with chemokine receptors, which are also GPCRs. As GPCRs can undergo heterologous desensitization, we have examined the ability of baclofen, a GABA(B) receptor selective agonist, to interfere with the function of pro-inflammatory chemokine receptors known to be upregulated in cutaneous inflammation. In vitro, baclofen reduces chemotaxis of human peripheral blood mononuclear cells towards CCL2, CCL5, CXCL10, CXCL2 and CX3CL1 in a dose-dependant manner. Protein kinase C inhibitors calphostin C and G0 6976 could reverse this effect, pointing towards the involvement of both calcium-dependent and -independent protein kinase C in baclofen-induced inhibition of chemokine receptors. In an in vivo model of contact hypersensitivity in C57BL/6 mice, intraperitoneal injection of baclofen markedly alleviated signs of inflammation as well as recruitment of neutrophils, monocytes and lymphocytes into the skin. This study demonstrates a new role for the GABA(B) receptor in inflammation, making it a potential new therapeutic target to treat inflammatory skin diseases.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Baclofen/pharmacology , Dermatitis, Allergic Contact/drug therapy , GABA-B Receptor Agonists , Animals , Cells, Cultured , Chemotaxis, Leukocyte/drug effects , Dermatitis, Allergic Contact/pathology , Dermatitis, Allergic Contact/physiopathology , Disease Models, Animal , Female , GABA Agonists/pharmacology , Humans , In Vitro Techniques , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/physiology , Mice , Mice, Inbred C57BL , Protein Kinase C/metabolism , Receptor Cross-Talk , Receptors, Chemokine/drug effects , Receptors, Chemokine/physiology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Resultante da cooperaçäo Brasil/Itália, a obra discute as experiências em saúde mental. Analisa os temas da: descentralizaçäo, açäo intersocial, cidadania, sistema locais de saúde, reforma psiquiátrica, desconstruçäo do aparato manicomial e avaliaçäo dos serviços (AMSB)
