Transcriptional regulation of type-2 metabotropic glutamate receptors: an epigenetic path to novel treatments for chronic pain Santina Chiechio 1 , Agata Copani 1, 2 , Magda Zammataro 1, 3 , Giuseppe Battaglia 4 , Robert W. Gereau IV 5 and Ferdinando Nicoletti 4, 6 1 Department of Pharmaceutical Sciences, University of Catania, Catania, Italy 2 I.B.B., CNR-Catania, Italy 3 PhD Program in Neuropharmacology, University of Catania, Catania, Italy 4 I.N.M. Neuromed, Pozzilli, Italy 5 Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA 6 Department of Physiology and Pharmacology, University ‘‘La Sapienza’’, Roma, Italy Activation of metabotropic glutamate 2 (mGlu2) recep- tors 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 neu- ropathic pain, but their use is limited by the develop- ment 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. Introduction Chronic pain, defined as persistent or intermittent pain lasting at least 3 months, affects approximately one-sixth of the population and causes a large socioeconomic burden with annual costs of $40–220 billion in the US [1–4]. In spite of the numerous analgesic drugs present in the market, including non-steroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, anticonvulsants, local anesthetics, N-methyl-D-aspartate receptor antagonists and others, the treatment outcome is highly variable, with a significant proportion of patients showing resistance to medication. For example, a reduced responsiveness to opioid analgesics is typically seen in patients with neuropathic pain, a particular type of pain that derives from structural or func- tional abnormalities of peripheral nerves or central nocicep- tive pathways [5]. Changes in the response to analgesic medication could reflect interindividual variations in drug absorption, distribution, metabolism and elimination, or polymorphisms in drug targets. In addition, prolonged use of opioids and other analgesic drugs can cause the development of tolerance (i.e. the need to increase the doses to maintain the clinical response), and, sometimes, unpre- dictable episodes of moderate-to-severe pain that break through the baseline pain medication. These drawbacks are inherent to the nature of all current analgesic drugs, which activate or inhibit G-protein-coupled receptors, ion channels, intracellular enzymes or membrane transporters. Analgesic drugs induce adaptive changes in their targets that develop within the context of the ‘‘pathological’’ neuro- plasticity associated with chronic pain (see below). In addition, most analgesic drugs are not ‘‘disease-dependent’’ because their targets are widespread both in the central nervous system (CNS) and peripheral organs. Metabotropic glutamate (mGlu) receptors are important players in pain regulation and a variety of pharmacological approaches are being evaluated for improved pain control. In addition to targeting specific mGlu receptors with exogenous drugs, there is a need for novel therapeutic strategies that reinforce endogenous analgesic mechanisms without the Opinion Glossary Nociceptive sensitization: refers to an increased gain of the pain neuraxis underlying different types of chronic pain, including inflammatory, dysfunc- tional and neuropathic pain. As a result of nociceptive sensitization, pain is amplified in response to noxious stimuli (primary hyperalgesia), spreads beyond the site of injury (secondary hyperalgesia), can be elicited by innocuous stimuli (allodynia) or can arise spontaneously. Whereas primary hyperalgesia reflects the development of peripheral sensitization at the site of tissue injury, secondary hyperalgesia and allodynia mainly reflect the development of central sensitization at the synapses between primary afferent fibers and secondary order sensory neurons in the dorsal horn of the spinal cord and in higher pain-regulatory centers [5,6,66,67]. TRPV1: is one of the approximately 30 members of the transient receptor potential (TRP) family of cation channels. TRPV1 expressed on peripheral nociceptors is the main endogenous transducer of noxious heat, and also responds to protons, and a series of lipid molecules termed ‘‘endovanilloids’’. Increase in the expression and/or activity of TRPV1 and other TRP channels contribute to processes of nociceptive sensitization [68,69]. Corresponding author: Nicoletti, F. (ferdinandonicoletti@hotmail.com). 0165-6147/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2009.12.003 Available online 11 January 2010 153