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

被引:67
作者
Chiechio, Santina
Copani, Agata
De Petris, Laura
Morales, Maria Elena P.
Nicoletti, Ferdinando
Gereau, Robert W. [1 ]
机构
[1] Washington Univ, Pain Ctr, St Louis, MO 63130 USA
[2] Washington Univ, Sch Med, Dept Anaesthesiol, St Louis, MO USA
[3] Univ Catania, Dept Pharmaceut Sci, Catania, Italy
[4] CNR, IBB, Catania, Italy
[5] Washington Univ, Sch Med, Dept Pediat, Renal Div Unit, St Louis, MO 63110 USA
[6] Univ Roma La Sapienza, Dept Human Physiol & Pharmacol, Rome, Italy
[7] INM Neuromed, Pozzilli, Italy
[8] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA
来源
MOLECULAR PAIN | 2006年 / 2卷
关键词
D O I
10.1186/1744-8069-2-20
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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-kappa B). A single application of LAC (250 mu M) 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-kappa B binding to DNA by caffeic acid phenethyl ester (CAPE) (2.5 mu g/ 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-.B 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-.B 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-.B transcriptional machinery, and that agents that increase acetylation and activation of NF-.B transcription factors might induce analgesia via upregulation of mGlu2 in DRG neurons.
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页数:9
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