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

Abstract

Most -opioid receptor agonists recruit ␤-arrestin2, with some exceptions such as morphine. Surprisingly, however, the acute analgesic effect of morphine is enhanced in the absence of ␤-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 ␤-arrestin2 knockout mice. We report that, in these mice, presynaptic inhibition of evoked inhibitory postsynaptic currents was enhanced, whereas postsynaptic G protein-coupled K ؉ (Kir3͞GIRK) currents were unaffected. The frequency, but not amplitude, of miniature inhibitory postsynaptic currents was increased in ␤-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, ␤-arrestin2 attenuates presynaptic inhibition by opioids independent ofopioid receptor-driven recruitment, which may make ␤-arrestin2 a promising target for regulating analgesia.synaptic transmission ͉ -opioid receptors ͉ locus coeruleus ͉ periaqueductal gray ͉ analgesia A rrestin interaction with phosphorylated -opioid receptors (MORs) prompts desensitization of signaling by receptor uncoupling from G proteins followed by endocytosis (1). In addition, it has been found recently that during adrenergic signaling, ␤-arrestin2 forms a complex with phosphodiesterase 4 (PDE4). PDE4 is the cAMP-specific phosphodiesterase (2, 3); its interaction with ␤-arrestin2 thereby delivers the rate-limiting enzyme for cAMP degradation to the receptor site and thus quenches protein kinase A (PKA)-dependent processes (4-6).In contrast to most other MOR agonists, morphine does not lead to ␤-arrestin recruitment and subsequent MOR internalization (7, 8). Nevertheless, opioid-mediated analgesia is strongly enhanced in ␤-arrestin2 knockout (KO) animals (9), but not in ␤-arrestin1 KO animals (8). The effects of morphine are mediated by two cellular functions localized in distinct compartments. Whereas activation of MORs expressed on the soma and dendrites leads to strong hyperpolarization of the neuron, MORs on synaptic terminals regulate transmitter release, in particular at GABAergic synapses (10). The molecular effectors have been shown to differ in the two cellular compartments. Postsynaptic inhibition is mediated by the activation of Kir3͞GIRK channels (11,12). Presynaptic inhibition, on the other hand, is caused by an inhibition of calcium channels (13), direct effects on the release machinery downstream of calcium entry (14), or activation of voltage-gated potassium channels (15).Here, we have characterized the effects of the two MOR agonists, morphine and fentanyl, in acute slices of the locus coeruleus (LC) and the periaqueductal gray (PAG) of ␤-arrestin2 KO animals. The LC was chosen because it consists of a homogeneous population of adrenergic neurons that are ideal for studying pre-and postsyna...

Tolerance to Repeated Morphine Administration Is Associated with Increased Potency of Opioid Agonists

“…Mice lacking b-arrestin2 also display increased GTPgS binding in PAG membranes without a change in m-opioid receptor density (Bohn et al, 1999(Bohn et al, , 2000. Although acute postsynaptic sensitivity of m-opioid receptor activation of GIRK channels has been reported to be the same in barrestin2 knock-out and wild-type mice (Bradaia et al, 2005), m-opioid receptor supersensitivity may only occur after prolonged, or repeated morphine treatment and not with acute administration.…”

Arrestin Is Required for Agonist-induced Trafficking of Voltage-dependent Calcium Channels

“…␤-Arrestin 2 knockout mice exhibit several phenotypes associated with neuronal signaling such as enhanced sensitivity to morphine in pain assays (31), enhanced reward response to opioids (32), and decrease in dopaminemediated locomotor responses (33). Through interaction with phosphodiesterase 4, ␤-arrestin 2 regulates opioid-mediated presynaptic inhibition by regulating synaptic release probability (34). Recently it has been shown that ␤-arrestin 2 associates with Akt and phosphatase PP2A to mediate dopaminergic responses (33).…”

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

“…Phosphodiesterase-4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cyclic AMP (cAMP) and is critical in controlling its intracellular concentration, is involved in various central nervous system (CNS) processes, including depression , learning and memory (Barad et al, 1998), anxiety (Beer et al, 1972), and analgesia (Bradaia et al, 2005). Administration of PDE4 inhibitors such as rolipram produces antidepressant-like effects (Zhang et al, 2002(Zhang et al, , 2006, reverses memory deficits induced pharmacologically, physically, or genetically (Bourtchouladze et al, 2003;Imanishi et al, 1997;Zhang et al, 2000Zhang et al, , 2004, alters anxiogenic-like behavior (Imaizumi et al, 1994;Silvestre et al, 1999a), and induces analgesia in rodents (Kumar et al, 2000).…”