Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain.

摘要: Knowing that expression of metabotropic glutamate 2 (mGlu2) receptors in the dorsal root ganglia is regulated by acetylation mechanisms, we examined effect two selective and chemically unrelated histone deacetylase (HDAC) inhibitors, N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (MS-275) suberoylanilide hydroamic acid (SAHA), a mouse model persistent inflammatory pain. Although single subcutaneous injection MS-275 (3 mg/kg) or SAHA (5-50 was ineffective, 5-day treatment with either HDAC inhibitors substantially reduced nociceptive response second phase formalin test, which reflects development central sensitization horn spinal cord. Analgesia abrogated mGlu2/3 receptor antagonist (alphaS)-alpha-amino-alpha-[(1S,2S)-2-carboxycyclopropyl]-9H-xantine-9-propanoic (LY341495; 1 mg/kg, i.p.), inactive per se. Both up-regulated mGlu2 ganglion (DRG) cord under conditions they caused analgesia, without changing mGlu1a, mGlu4, mGlu5 receptors. Induction DRG to associated increased p65/RelA on lysine 310, process enhances transcriptional activity at nuclear factor-kappaB-regulated genes. Transcription gene known be activated neurons. We conclude inhibition produces analgesia up-regulating DRG, an results from amplification NF-kappaB activity. These data provide first evidence cause suggest HDACs are potential targets for epigenetic