Activation of metabotropic glutamate 2 (mGlu2) receptors inhibits pain transmission at the synapses between primary afferent fibers and neurons in the dorsal horn of the spinal cord. In addition, mGlu2 receptors are found in peripheral nociceptors, and in pain-regulatory centers of the brain stem and forebrain. mGlu2 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 could be based on the transcriptional regulation of mGlu2 receptors via the acetylation-promoted activation of the p65/RelA transcription factor. "Epigenetic" drugs that increase mGlu2 receptor expression, including l-acetylcarnitine and inhibitors of histone deacetylases, have a different analgesic profile with no tolerance to the therapeutic effect after repeated dosing.