title: beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids.
abstract: Most mu-opioid receptor agonists recruit beta-arrestin2, with some exceptions such as morphine. Surprisingly, however, the acute analgesic effect of morphine is enhanced in the absence of beta-arrestin2. To resolve this paradox, we examined the effects of morphine and fentanyl in acute brain slices of the locus coeruleus and the periaqueductal gray from beta-arrestin2 knockout mice. We report that, in these mice, presynaptic inhibition of evoked inhibitory postsynaptic currents was enhanced, whereas postsynaptic G protein-coupled K(+) (Kir3/GIRK) currents were unaffected. The frequency, but not amplitude, of miniature inhibitory postsynaptic currents was increased in beta-arrestin2 knockout mice, indicating a higher release probability compared to WT mice. The increased release probability resulted from increased cAMP levels because of impaired phosphodiesterase 4 function and conferred an enhanced efficacy of morphine to inhibit GABA release. Thus, beta-arrestin2 attenuates presynaptic inhibition by opioids independent of mu-opioid receptor-driven recruitment, which may make beta-arrestin2 a promising target for regulating analgesia.
authors.affiliation: Department of Basic Neurosciences, University of Geneva, CH 1211 Geneva, Switzerland.
authors.forename: Amyaouch
authors.initials: A
authors.lastname: Bradaïa
authors.forename: Frédérique
authors.initials: F
authors.lastname: Berton
authors.forename: Serge
authors.initials: S
authors.lastname: Ferrari
authors.forename: Christian
authors.initials: C
authors.lastname: Lüscher
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000502:physiology*; D000818:Animals; D019390:Arrestins / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005283:Fentanyl / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009433:Neural Inhibition; D011336:Probability; D009435:Synaptic Transmission / Q000187:drug effects*; D000071557:beta-Arrestins; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D019390:Arrestins; D000071557:beta-Arrestins; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005283:Fentanyl
references.citation: Neuron. 1992 Aug;9(2):325-35
references.pmid: 1497896
references.citation: Neuron. 1997 Sep;19(3):687-95
references.pmid: 9331358
references.citation: J Neurosci. 1994 Jan;14(1):310-7
references.pmid: 7506766
references.citation: Science. 1994 Sep 23;265(5180):1878-82
references.pmid: 7916482
references.citation: Br J Pharmacol. 1995 Jul;115(6):925-32
references.pmid: 7582522
references.citation: J Physiol. 1996 Jan 15;490 ( Pt 2):383-9
references.pmid: 8821137
references.citation: Nature. 1997 Dec 11;390(6660):611-4
references.pmid: 9403690
references.citation: Annu Rev Pharmacol Toxicol. 1998;38:201-27
references.pmid: 9597154
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9914-9
references.pmid: 9707575
references.citation: J Neurosci. 1998 Dec 15;18(24):10269-76
references.pmid: 9852564
references.citation: Science. 1999 Dec 24;286(5449):2495-8
references.pmid: 10617462
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4674-9
references.pmid: 11917119
references.citation: J Neurosci. 2002 Jun 1;22(11):4328-34
references.pmid: 12040038
references.citation: Nat Rev Mol Cell Biol. 2002 Sep;3(9):710-8
references.pmid: 12209131
references.citation: J Clin Invest. 2002 Oct;110(7):1045-52
references.pmid: 12370283
references.citation: Science. 2002 Oct 25;298(5594):834-6
references.pmid: 12399592
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):271-6
references.pmid: 12496346
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):940-5
references.pmid: 12552097
references.citation: Biochem J. 2003 Feb 15;370(Pt 1):1-18
references.pmid: 12444918
references.citation: J Biol Chem. 2003 Feb 21;278(8):5493-6
references.pmid: 12493749
references.citation: Neuroscience. 2003;119(1):33-42
references.pmid: 12763066
references.citation: Nature. 2003 Aug 14;424(6950):775-8
references.pmid: 12917685
references.citation: Neuropharmacology. 2003 Oct;45(5):575-84
references.pmid: 12941371
references.citation: Mol Cell Neurosci. 2003 Oct;24(2):517-23
references.pmid: 14572471
references.citation: J Neurosci. 2003 Nov 19;23(33):10515-20
references.pmid: 14627635
references.citation: J Biol Chem. 2003 Dec 5;278(49):49230-8
references.pmid: 14500724
references.citation: Brain Res. 2004 Jan 30;997(1):67-78
references.pmid: 14715151
references.citation: Nat Neurosci. 2004 Feb;7(2):153-9
references.pmid: 14745451
references.citation: Neuron. 2004 Feb 5;41(3):417-29
references.pmid: 14766180
references.citation: Trends Pharmacol Sci. 2004 Mar;25(3):158-63
references.pmid: 15019272
references.citation: J Neurosci. 2004 Jun 2;24(22):5202-8
references.pmid: 15175390
references.citation: Nat Rev Neurosci. 2004 Jul;5(7):565-75
references.pmid: 15208698
references.citation: Mol Pharmacol. 2004 Jul;66(1):106-12
references.pmid: 15213301
references.citation: Annu Rev Neurosci. 2004;27:107-44
references.pmid: 15217328
references.citation: J Neurophysiol. 1986 Nov;56(5):1397-410
references.pmid: 3025380
references.citation: Biochem J. 1987 Jan 15;241(2):535-41
references.pmid: 3036066
references.citation: Pharmacol Biochem Behav. 1991 Apr;38(4):753-8
references.pmid: 1714608
references.citation: Neurosci Lett. 1991 May 27;126(2):179-83
references.pmid: 1922930
references.citation: J Physiol. 1997 Jan 15;498 ( Pt 2):463-72
references.pmid: 9032693
references.citation: Neuron. 1992 Nov;9(5):919-27
references.pmid: 1358131