All current analgesic drugs target functional proteins (such as ion channels, G-protein coupled receptors, membrane transporters, and intracellular enzymes) that are widespread and undergo plastic modifications in response to exogenous ligands. As a result, tolerance and serious adverse effects are frequently encountered with analgesic drugs. In addition, there are types of pain, such as neuropathic pain, that may be refractory to multiple classes of analgesics, and are difficult to treat.

The study of group-II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) has disclosed a new strategy for the treatment of chronic pain. mGlu2 and mGlu3 receptors are coupled to Gi proteins and are preferentially localized on axon terminals, where they negatively regulate neurotransmitter release. Activation of mGlu2/3 receptors inhibits pain transmission at the synapses between primary afferent fibres and neurons in the dorsal horn of the spinal cord. As expected, mGlu2/3 receptor agonists produce analgesia in models of inflammatory and neuropathic pain but their use is limited by the development of tolerance.

A new therapeutic strategy stems from the finding that the acetylating agent, L-acetylcarnitine (LAC), that has been shown to have analgesic activity, enhances the expression of mGlu2 receptors in the dorsal root ganglia (DRG), dorsal horn of the spinal cord., and cerebral cortex. Interestingly, LAC-induced analgesia is abrogated by a single injection of the mGlu2/3 antagonist, LY341495, suggesting that LAC relieves pain through the induction of mGlu2 receptors.

LAC up-regulates mGlu2 receptors by acetylating the transcription factor p65/RelA of the nuclear factor-kB (NFkB) family. Acetylation/deacetylation processes of p65/RelA are mediated by histone acetyl transferases and histone deacetylases (HDACs), respectively. We have shown that HDAC-1 and -2 are expressed in DRG neurons and that the HDAC inhibitors, SAHA and MS-275, up-regulate mGlu2 receptors in the DRG and spinal cord, and relieve pain in mice subjected to the formalin test.

These findings suggest that the epigenetic control of mGlu2 receptors may be targeted by novel analgesic drugs and that "epigenetic" drugs could optimize the analgesic activity of receptor agonists by increasing the receptor reserve of mGlu2 receptors along the pain neuraxis, thereby limiting the development of tolerance in response to receptor activation.