Research

Transcriptional regulation of metabotropic glutamate receptor 2/3 expression by the NF-κB pathway in primary dorsal root ganglia neurons: a possible mechanism for the analgesic effect of L-acetylcarnitine

Santina Chiechio¹ , Agata Copani^2,3 , Laura De Petris⁴ , Maria Elena P Morales¹ , Ferdinando Nicoletti^5,6 and Robert W Gereau IV^1,7

¹  Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis MO, USA

²  Department of Pharmaceutical Sciences, University of Catania, Catania, Italy

³  I.B.B., CNR-Catania, Italy

⁴  Department of Pediatrics, Renal Division Unit, Washington University School of Medicine, St. Louis, MO, USA

⁵  Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Rome, Italy

⁶  I.N.M. Neuromed, Pozzilli, Italy

⁷  Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, USA

author email corresponding author email

Molecular Pain 2006, 2:20doi:10.1186/1744-8069-2-20

Published:	9 June 2006

Abstract

L-acetylcarnitine (LAC), a drug utilized for the treatment of neuropathic pain in humans, has been shown to induce analgesia in rodents by up-regulating the expression of metabotropic glutamate receptor 2 (mGlu2) in dorsal root ganglia (DRG). We now report that LAC-induced upregulation of mGlu2 expression in DRG cultures involves transcriptional activation mediated by nuclear factor-kappaB (NF-κB). A single application of LAC (250 μM) to DRG cultures induced a transient increase in mGlu2 mRNA, which was observable after 1 hour and was no longer detectable after 1 to 4 days. In contrast, LAC treatment had no effect on mGlu3 mRNA expression. Pharmacological inhibition of NF-κB binding to DNA by caffeic acid phenethyl ester (CAPE) (2.5 μg/ml for 30 minutes) reduced the constitutive expression of mGlu2 and mGlu3 mRNA after 1–4 days and reduced the constitutive expression of mGlu2/3 protein at 4 days. This evidence combined with the expression of p65/RelA and c-Rel in DRG neurons indicated that expression of mGlu2 and mGlu3 is endogenously regulated by the NF-κB family of transcription factors. Consistent with this idea, the transient increase in mGlu2 mRNA induced by LAC after 1 hour was completely suppressed by CAPE. Furthermore, LAC induced an increase in the acetylation of p65/RelA, a process that enhances the transcriptional activity of p65/RelA. These results are consistent with the hypothesis that LAC selectively induces the expression of mGlu2 by acting as a donor of acetyl groups, thus enhancing the activity of the NF-κB family of transcription factors. Accordingly, we show that carnitine, which has no effect on pain thresholds, had no effect on p65/RelA acetylation and did not enhance mGlu2 expression. Taken together, these results demonstrate that expression of mGlu2 and mGlu3 mRNA is regulated by the NF-κB transcriptional machinery, and that agents that increase acetylation and activation of NF-κB transcription factors might induce analgesia via upregulation of mGlu2 in DRG neurons.