title: Nerve Injury Diminishes Opioid Analgesia through Lysine Methyltransferase-mediated Transcriptional Repression of μ-Opioid Receptors in Primary Sensory Neurons.
abstract: The μ-opioid receptor (MOR, encoded by Oprm1) agonists are the mainstay analgesics for treating moderate to severe pain. Nerve injury causes down-regulation of MORs in the dorsal root ganglion (DRG) and diminishes the opioid effect on neuropathic pain. However, the epigenetic mechanisms underlying the diminished MOR expression caused by nerve injury are not clear. G9a (encoded by Ehmt2), a histone 3 at lysine 9 methyltransferase, is a key chromatin regulator responsible for gene silencing. In this study, we determined the role of G9a in diminished MOR expression and opioid analgesic effects in animal models of neuropathic pain. We found that nerve injury in rats induced a long-lasting reduction in the expression level of MORs in the DRG but not in the spinal cord. Nerve injury consistently increased the enrichment of the G9a product histone 3 at lysine 9 dimethylation in the promoter of Oprm1 in the DRG. G9a inhibition or siRNA knockdown fully reversed MOR expression in the injured DRG and potentiated the morphine effect on pain hypersensitivity induced by nerve injury. In mice lacking Ehmt2 in DRG neurons, nerve injury failed to reduce the expression level of MORs and the morphine effect. In addition, G9a inhibition or Ehmt2 knockout in DRG neurons normalized nerve injury-induced reduction in the inhibitory effect of the opioid on synaptic glutamate release from primary afferent nerves. Our findings indicate that G9a contributes critically to transcriptional repression of MORs in primary sensory neurons in neuropathic pain. G9a inhibitors may be used to enhance the opioid analgesic effect in the treatment of chronic neuropathic pain.
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Laumet
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030 huilinpan@mdanderson.org.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000698:Analgesia; D000818:Animals; D005260:Female; D005727:Ganglia, Spinal / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D059348:Peripheral Nerve Injuries / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D006657:Histones; C404943:Oprm protein, mouse; C485765:Oprm1 protein, rat; D017450:Receptors, Opioid, mu; C577330:Ehmt2 protein, rat; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: electrophysiology; epigenetics; neuron; neurophysiology; opiate opioid; pain