PDE4 inhibition enhances function of mu opioid agonists - sci.life-extension

Mesej daripada perbincangan PDE4 inhibition enhances function of mu opioid agonists
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Subject: PDE4 inhibition enhances function of mu opioid agonists
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This might explain the reported synergy between low-dose naltrexone and 
rolipram.

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, 
Switzerland.

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