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

摘要

Most μ-opioid receptor agonists recruit β-arrestin2, with some exceptions such as morphine. Surprisingly, however, the acute analgesic effect of morphine is enhanced in the absence of β-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 β-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 β-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, β-arrestin2 attenuates presynaptic inhibition by opioids independent of μ-opioid receptor-driven recruitment, which may make β-arrestin2 a promising target for regulating analgesia.