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This might explain the reported synergy between low-dose naltrexone and

Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3034-9. Epub 2005 Feb 17

beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic
release probability and presynaptic inhibition by opioids.
* Bradaia A,
* Berton F,
* Ferrari S,
* Luscher C.

Department of Basic Neurosciences, University of Geneva, CH 1211 Geneva,

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.

PMID: 15718284