A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states.
Activity-dependent changes in neurons of the rat superficial dorsal horn are crucial for the induction and maintenance of neuropathic and inflammatory pain states. To identify the molecular mechanisms underlying this sensitization of superficial dorsal horn neurons, we undertook a genome-wide microarray profiling of dorsal horn gene transcripts at various times after induction of peripheral inflammation of the rat ankle joint. At early time points, upregulation of gene expression dominated, but by 7 d, downregulation was predominant. Two to 24 h after inflammation, we identified a small number of highly upregulated transcripts previously shown to be repressed by the Methyl-CpG-binding protein 2 (MeCP2), including serum- and glucocorticoid-inducible kinase (SGK1) and FK 506 binding protein 5, genes known to be important in experience-dependent plasticity. A decrease in expression of SIN3A, a corepressor in the MeCP2 silencing complex, was also found after inflammation. Phosphorylation of MeCP2 regulates activity-dependent gene transcription, and crucially we found that MeCP2 was phosphorylated in lamina I projection neurons 1 h after induction of peripheral inflammation. Lamina I projection neurons have been shown to be essential for the development of most pain states. SGK1 protein was also localized, in part, to lamina I projection neurons, and its expression in the superficial dorsal horn increased after inflammation. Furthermore, antisense knock-down of SGK1 delayed the onset of inflammatory hyperalgesia by 24 h at least. Our results uncover an unexpected complexity in the regulation of gene expression, including the modulation of transcriptional repression, that accompanies development and maintenance of an inflammatory pain state.
Géranton
Sandrine M
SM
Department of Anatomy and Developmental Biology and London Pain Consortium, UCL, London WC1E 6BT, United Kingdom. ucgasmg@ucl.ac.uk
Morenilla-Palao
Cruz
C
Hunt
Stephen P
SP
D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000097:blood / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics*; D010146:Pain / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010147:Pain Measurement / Q000379:methods; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000097:blood / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D018836:Inflammation Mediators; D051783:Methyl-CpG-Binding Protein 2; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases