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

Berton, Frederique
Published in Proceedings of the National Academy of Sciences. 2005, vol. 102, no. 8, p. 3034-3039
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.
Keywords AnimalsArrestins/ physiologyCyclic AMP/physiologyCyclic AMP-Dependent Protein Kinases/physiologyCyclic Nucleotide Phosphodiesterases, Type 4Fentanyl/ pharmacologyLocus Coeruleus/ drug effects/physiologyMembrane Potentials/drug effectsMiceMice, Inbred C57BLMorphine/ pharmacologyNeural InhibitionProbabilitySynaptic Transmission/ drug effectsGamma-Aminobutyric Acid/secretion
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PMID: 15718284

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Deposited on : 2010-08-06

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