Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Robichaud, Annette; Stamatiou, Panagiota B.; Jin, S.-L. Catherine; Lachance, Nicholas; Macdonald, D.D.; Laliberté, France; Liu, Susana; Huang, Zheng; Conti, Marco; Chen, Chan

doi:10.1172/jci0215506

Cited by 261 publications

(153 citation statements)

References 33 publications

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“…This mechanism may regulate the analgesic efficacy of opioids without direct recruitment of ␤-arrestin2 by MORs. Our findings support early data in rodents (38), as well as more recent findings including studies on PDE4 KO mice (39), and human clinical trials indicating that centrally active PDE4 …”

Section: Pre-and Postsynaptic Inhibition Of Lc Neurons By Morphinesupporting

confidence: 92%

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

Bradaı̈a

Berton

Ferrari

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Pre-and Postsynaptic Inhibition Of Lc Neurons By Morphinesupporting

confidence: 92%

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

Bradaı̈a

Berton

Ferrari

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, reversal of ␣2-adrenergic receptor-induced anesthesia has been used as a surrogate test for emesis in mouse and rat, which do not exhibit the emetic reflex. PDE4D but not PDE4B ablation impacts this surrogate response, again suggesting that the emetic response is the result of PDE4D inhibition (44). Thus, drugs that preferentially inhibit PDE4B over PDE4D should retain many of the beneficial anti-inflammatory effects with fewer unwanted CNS effects.…”

Section: Discussionmentioning

confidence: 99%

Specific Role of Phosphodiesterase 4B in Lipopolysaccharide-Induced Signaling in Mouse Macrophages

Jin

Lan

Zoudilova

et al. 2005

The Journal of Immunology

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214

201

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Cyclic nucleotide signaling functions as a negative modulator of inflammatory cell responses, and type 4 phosphodiesterases (PDE4) are important regulators of this pathway. In this study, we provide evidence that only one of the three PDE4 genes expressed in mouse peritoneal macrophages is involved in the control of TLR signaling. In these cells, LPS stimulation of TLR caused a major up-regulation of PDE4B but not the paralogs PDE4A or PDE4D. Only ablation of PDE4B impacted LPS signaling and TNF-α production. TNF-α mRNA and protein were decreased by >50% in PDE4B−/−, but not in PDE4A−/− or PDE4D−/− macrophages. The PDE4 selective inhibitors rolipram and roflumilast had no additional inhibitory effect in macrophages deficient in PDE4B, but suppressed the TNF-α response in the other PDE4 null cells. The inhibition of TNF-α production that follows either genetic ablation or acute inhibition of PDE4B is cAMP-dependent and requires protein kinase A activity. However, no global changes in cAMP concentration were observed in the PDE4B−/− macrophages. Moreover, ablation of PDE4B protected mice from LPS-induced shock, suggesting that altered TLR signaling is retained in vivo. These findings demonstrate the highly specialized function of PDE4B in macrophages and its critical role in LPS signaling. Moreover, they provide proof of concept that a PDE4 inhibitor with subtype selectivity retains useful pharmacological effects.

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“…A clinical trial of rolipram reported acceptable tolerance levels at clinically relevant doses (Fleischhacker, Hinterhuber et al 1992). In clinical and preclinical trials, the main human PDE4 inhibitor side effect, thought to be due to PDE4D activity (Robichaud, Savoie et al 2002;Robichaud, Stamatiou et al 2002;Conti, Richter et al 2003), is emesis at clinical doses while rats are more susceptible to toxic effects like arteriopathy. One explanation for this effect is the reduced PDE4 enzyme activity in humans relative to monkeys and rats (Bian, Zhang et al 2004).…”

Section: Camp Therapymentioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

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Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Cited by 261 publications

References 33 publications

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

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

Specific Role of Phosphodiesterase 4B in Lipopolysaccharide-Induced Signaling in Mouse Macrophages

The cyclic AMP phenotype of fragile X and autism

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