mGlu2 mRNA expression has been shown to be increased by LAC both in the dorsal horn of the rat spinal cord and in the DRG (Chiechio et al., 2002, and this study). Here we demonstrate that NF-κB transcriptional activity influences the constitutive expression of mGlu2/3 in DRG cultures and that LAC-induced up-regulation of mGlu2 expression is also dependent on NF-κB activity.
NF-κB activity is reciprocally regulated by RelA/p65 acetylation and deacetylation, which may be mediated by p300 or CBP acetyltransferases and histone deacetylase 3 . In its acetylated state, NF-κB is resistant to the inhibitory effect of I-κB and therefore its binding affinity to DNA containing NF-κB binding sites is enhanced [20, 22]. LAC, behaving as donor of acetyl groups, could induce mGlu2 mRNA expression by promoting the acetylation of p65/Rel-A. This hypothesis is supported by our results showing that LAC treatment induces an increase in the levels of acetylated p65/Rel-A in DRG cultures. The mechanism by which LAC increases p65/Rel-A acetylation levels remains to be determined; however, the observation that L-carnitine was unable to affect p65/Rel-A acetylation in DRG cultures suggests that the acetyl moiety of the drug is involved in this mechanism. In vivo studies demonstrating that the analgesic effect of LAC is not shared by the non acetylated derivative L-carnitine  also corroborate our hypothesis that the acetyl moiety is of fundamental importance for promoting the transcriptional activity of NF-κB and therefore the induction of mGlu2, which in turn are responsible for the analgesic effect of LAC [10, 11].
Although the basal expression of both mGlu2 and mGlu3 mRNA was regulated by NF-κB, LAC induced mGlu2, but not mGlu3, mRNA expression. This evidence suggested that NF-κB-dependent mGlu3 transcription did not involve p65/Rel-A elements. Hence, similar to their human homologs, the promoter regions of mouse GRM2 and GRM3 genes might bind different NF-κB family members. Consistent with this hypothesis, the NF-κB family member c-Rel, which is not activated by acetylation, is expressed in cultured DRG neurons (Fig 2B). Future studies should examine whether mGlu3 expression is regulated by c-Rel or another NF-κB family member.
NF-κB plays a pivotal role in regulating pro-inflammatory cytokine gene expression , and is thus involved in the genesis and persistence of pain after nerve injury . NF-κB is also required for electroacupuncture-induced analgesia , and it is involved in inflammation-induced analgesia through the upregulation of μ-opioid receptors . Whether mGlu2/3 modulation by the NF-κB pathway occurs under conditions of inflammatory pain still has to be determined. Interestingly, changes in the expression of metabotropic glutamate receptors during inflammation have been reported by several authors. In particular, an increased expression of mGlu3 mRNA and protein after peripheral inflammation has been demonstrated in the rat spinal cord [31, 32]. Since NF-κB activation can be triggered by inflammatory mediators in neurons [33, 34], it is likely that the NF-κB pathway is involved in the regulation of metabotropic glutamate receptors observed in vivo.
We now suggest that NF-κB-mediated mGlu2 upregulation might be responsible for the analgesic effects of LAC against peripheral nerve injury and in acute thermal pain . Anticonvulsant and antidepressant drugs are commonly used to treat neuropathic pain syndromes [35, 36]. Remarkably, many of these drugs are able to inhibit histone deacetylase (HDAC) and therefore increase protein acetylation. Among anticonvulsants used in chronic pain therapy, carbamazepine, valproic acid and topiramate are known to inhibit HDAC and increase protein acetylation levels [37, 38]. Whether increased acetylation leads to the upregulation of group II metabotropic glutamate receptors has to be determined. Interestingly, the tricyclic antidepressant, imipramine, which is also able to up-regulate group II metabotropic glutamate receptors  has recently been shown to increases histone acetylation by down-regulating HDACs . The present results combined with the previous studies described above suggest the possibility that acetylating agents might be beneficial as analgesics in chronic pain conditions.