beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids.
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.
Bradaïa
Amyaouch
A
Department of Basic Neurosciences, University of Geneva, CH 1211 Geneva, Switzerland.
Berton
Frédérique
F
Ferrari
Serge
S
Lüscher
Christian
C
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
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
Neuron. 1992 Aug;9(2):325-35
1497896
Neuron. 1997 Sep;19(3):687-95
9331358
J Neurosci. 1994 Jan;14(1):310-7
7506766
Science. 1994 Sep 23;265(5180):1878-82
7916482
Br J Pharmacol. 1995 Jul;115(6):925-32
7582522
J Physiol. 1996 Jan 15;490 ( Pt 2):383-9
8821137
Nature. 1997 Dec 11;390(6660):611-4
9403690
Annu Rev Pharmacol Toxicol. 1998;38:201-27
9597154
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9914-9
9707575
J Neurosci. 1998 Dec 15;18(24):10269-76
9852564
Science. 1999 Dec 24;286(5449):2495-8
10617462
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4674-9
11917119
J Neurosci. 2002 Jun 1;22(11):4328-34
12040038
Nat Rev Mol Cell Biol. 2002 Sep;3(9):710-8
12209131
J Clin Invest. 2002 Oct;110(7):1045-52
12370283
Science. 2002 Oct 25;298(5594):834-6
12399592
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):271-6
12496346
Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):940-5
12552097
Biochem J. 2003 Feb 15;370(Pt 1):1-18
12444918
J Biol Chem. 2003 Feb 21;278(8):5493-6
12493749
Neuroscience. 2003;119(1):33-42
12763066
Nature. 2003 Aug 14;424(6950):775-8
12917685
Neuropharmacology. 2003 Oct;45(5):575-84
12941371
Mol Cell Neurosci. 2003 Oct;24(2):517-23
14572471
J Neurosci. 2003 Nov 19;23(33):10515-20
14627635
J Biol Chem. 2003 Dec 5;278(49):49230-8
14500724
Brain Res. 2004 Jan 30;997(1):67-78
14715151
Nat Neurosci. 2004 Feb;7(2):153-9
14745451
Neuron. 2004 Feb 5;41(3):417-29
14766180
Trends Pharmacol Sci. 2004 Mar;25(3):158-63
15019272
J Neurosci. 2004 Jun 2;24(22):5202-8
15175390
Nat Rev Neurosci. 2004 Jul;5(7):565-75
15208698
Mol Pharmacol. 2004 Jul;66(1):106-12
15213301
Annu Rev Neurosci. 2004;27:107-44
15217328
J Neurophysiol. 1986 Nov;56(5):1397-410
3025380
Biochem J. 1987 Jan 15;241(2):535-41
3036066
Pharmacol Biochem Behav. 1991 Apr;38(4):753-8
1714608
Neurosci Lett. 1991 May 27;126(2):179-83
1922930
J Physiol. 1997 Jan 15;498 ( Pt 2):463-72
9032693
Neuron. 1992 Nov;9(5):919-27
1358131