title: Regulation of mu-opioid receptors, G-protein-coupled receptor kinases and beta-arrestin 2 in the rat brain after chronic opioid receptor antagonism.
abstract: The aim of this study was to analyse the biochemical and behavioural consequences of chronic treatment with opioid receptor antagonists in rats. We have evaluated the respiratory depressant and antinociceptive effects of the mu-opioid agonist sufentanil, the density of brain mu-opioid receptors, and the expression of G-protein-coupled receptor kinases and beta-arrestin 2 in cerebral cortex and striatum, following sustained opioid receptor blockade. Our results demonstrate that 24 h after interruption of 7 days chronic infusion of naltrexone (120 microg/h), the respiratory depressant potency of the mu-opioid receptor agonist sufentanil was increased to a similar extent as the antinociceptive potency (about three-fold). This was accompanied by mu-opioid receptor up-regulation in several areas of the rat brain associated with opioid control of pain perception and breathing. Moreover, chronic treatment with either naltrexone (120 microg/h) or naloxone (120 microg/h) caused significant increases in the expression levels of G-protein-coupled receptor kinases types 2, 3, and 6, and of beta-arrestin 2 in brain cortex and striatum. Together our data suggest an increased constitutive receptor activity secondary to mu-opioid receptor up-regulation following chronic antagonist treatment.
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, E-39011 Santander, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Díaz
authors.forename: A
authors.initials: A
authors.lastname: Pazos
authors.forename: J
authors.initials: J
authors.lastname: Flórez
authors.forename: F J
authors.initials: FJ
authors.lastname: Ayesta
authors.forename: V
authors.initials: V
authors.lastname: Santana
authors.forename: M A
authors.initials: MA
authors.lastname: Hurlé
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D054770:G-Protein-Coupled Receptor Kinase 3; D054768:G-Protein-Coupled Receptor Kinases; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D017409:Sufentanil / Q000494:pharmacology; D013995:Time; D014018:Tissue Distribution; D051552:beta-Adrenergic Receptor Kinases; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: D000701:Analgesics, Opioid; C000605257:Arrb2 protein, rat; D019390:Arrestins; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009271:Naltrexone; D017409:Sufentanil; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D054770:G-Protein-Coupled Receptor Kinase 3; C517851:Grk3 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6