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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

DOI: 10.1186/1744-8069-2-20

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Abstract:

Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) induces antinociception in several pain models in rodents [1-5]. Consistent with these studies, we have shown that L-acetylcarnitine (LAC), a drug clinically effective in the treatment of neuropathic pain of various origins [6-9], up-regulates the expression of mGlu2 in the dorsal root ganglia (DRG) and in the dorsal horn (DH) of the spinal cord [10,11]. This has challenged the previous view that LAC increases pain thresholds and relieves neuropathic pain by enhancing brain acetylcholine synthesis [12] or by increasing the trophism of peripheral nerves [13,14]. Consistent with the "mGlu2 hypothesis of LAC-induced analgesia," the mGlu2/3 receptor antagonist, LY341495, prevents LAC-induced analgesia in rodents [10]. Interestingly, LAC selectively enhances the expression of mGlu2 receptors and has no effect on the expression of mGlu3 receptors [10,15], although these two receptor subtypes are highly homologous and share similar functions in the CNS [16]. This suggests that the expression of mGlu2 and mGlu3 is differentially regulated and that unraveling the nature of this difference may lead to the identification of new targets for the treatment of neuropathic pain.Analysis of the 5'-region upstream of the coding sequence of the human GRM2 gene (encoding mGlu2) [GenBank: AB045011], using the Transcription Factor Binding Sites Database TRANSFACT and TFSEARCH, revealed the presence of many potential regulatory elements for transcription factors of the NF-κB family, including p50 and p65/Rel-A, and for the coactivator p300. In contrast, only one binding site for the NF-κB family protein, c-Rel, and no binding sites for p65/RelA and p300 have been described in the putative promoter region of the human GRM3 gene encoding mGlu3 [17]. Hence, we focused on the NF-κB pathway in the search for mechanisms that account for the selective effect of LAC on mGlu2 expression.NF-κB consists of transcription factor

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