title: Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation.
abstract: The recently discovered endogenous peptide orphanin FQ/nociceptin (OFQ/N) activates the opioid receptor-like 1 (ORL1) receptor and produces diverse effects on pain perception. In addition to producing spinal analgesia, OFQ/N also exhibits an 'anti-opioid activity' against functional (supraspinal analgesia) and behavioral (conditioned place preference and withdrawal) properties of morphine. One manifestation of the behavioral changes resulting from chronic use of morphine is the upregulation of tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis), which contributes to the dramatic increases in catecholamine release in the target regions of the locus coeruleus (LC) and the ventral tegmental area (VTA). The present study sought to determine the molecular mechanism(s) by which OFQ/N modulates the chronic actions of morphine by utilizing human neuroblastoma cell lines [BE(2)-C and SH-SY5Y] that endogenously express TH, and mu and ORL1 receptors. Activation of mu or ORL1 receptors in these cells in turn activates extracellular signal-regulated protein kinases (ERKs), ERK1 and ERK2. Chronic activation of mu, but not ORL1, receptors upregulated TH levels in these cells as previously reported in rat brain. Morphine-induced TH upregulation was blocked upon inclusion of a MEK-1 (mitogen-activated protein kinase kinase-1) inhibitor (PD98059), confirming the role for ERKs in this adaptive response to morphine. Inclusion of OFQ/N during chronic morphine exposure also blocked morphine-induced TH upregulation. Furthermore, chronic OFQ/N exposure increased levels of the TH gene repressor, Oct-2, irrespective of the presence or absence of morphine. This report suggests a potential role for Oct-2 in mediating the anti-opioid actions of OFQ/N against the behavioral manifestations resulting from chronic use of morphine.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204-5037, USA.
authors.forename: Deepak R
authors.initials: DR
authors.lastname: Thakker
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Standifer
mesh_terms: D001921:Brain / Q000187:drug effects* / Q000201:enzymology* / Q000503:physiopathology; D002395:Catecholamines / Q000378:metabolism; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009021:Morphine Dependence / Q000201:enzymology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D050813:Octamer Transcription Factor-2; D018847:Opioid Peptides / Q000378:metabolism / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D002395:Catecholamines; D004268:DNA-Binding Proteins; D020928:Mitogen-Activated Protein Kinases; D009020:Morphine; D050813:Octamer Transcription Factor-2; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C058435:POU2F2 protein, human; C489205:Pou2f2 protein, rat; C000722283:OPRL1 protein, human