beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids

Article Article scientifique Article beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids eng 2005 author Bradaia Amyaouch 562574 author Berton Frederique author Ferrari Serge Livio 24314 author Luescher Christian 132337 3034-3039 10.1073/pnas.0406632102 15718284 0027-8424 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC549451/pdf/pnas-0406632102.pdf 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. Animals Arrestins/ physiology Cyclic AMP/physiology Cyclic AMP-Dependent Protein Kinases/physiology Cyclic Nucleotide Phosphodiesterases, Type 4 Fentanyl/ pharmacology Locus Coeruleus/ drug effects/physiology Membrane Potentials/drug effects Mice Mice, Inbred C57BL Morphine/ pharmacology Neural Inhibition Probability Synaptic Transmission/ drug effects Gamma-Aminobutyric Acid/secretion Dewey 616.8 Dewey 616 53 Département de neurosciences fondamentales 21A 56 Département de médecine 221 false Proceedings of the National Academy of Sciences of the United States of America 102 8 c4048782-00f3-4cec-a643-f1805c56fa5d Article Restricted file1.pdf 513800 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de neurosciences fondamentales Faculté de médecine / Section de médecine clinique / Département de médecine

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beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids	Proceedings of the National Academy of Sciences of the United States of America			2005	572	0

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Bradaia, Amyaouch