The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice

Scherrer, Grégory; Befort, Katia; Contet, Candice; Becker, Jérôme A.J.; Matifas, Audrey; Kieffer, Brigitte

doi:10.1111/j.0953-816x.2004.03339.x

Cited by 73 publications

(73 citation statements)

References 49 publications

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“…For Western blot analysis, 40 g of protein from brain membrane preparations (43) were incubated at 65°C for 5 min and loaded on a 12% polyacrylamide gel. After transfer, membranes were incubated at 4°C overnight with an anti-GFP rabbit polyclonal antibody (1 g͞ml; Abcam Inc., Cambridge, MA) in blocking solution (5% milk͞0.2% Tween 20͞PBS).…”

Section: Methodsmentioning

confidence: 99%

“…Saturation experiments were performed with [ 3 H]naltrindole (PerkinElmer) on brain membrane preparations as described (43). Agonist stimulated [ 35 S]GTP␥S (PerkinElmer) binding assay was carried out with SNC80 (Tocris Cookson, Bristol, U.K), deltorphin II (Sigma), and Met-enkephalin (Sigma) on brain membrane preparations as detailed in ref.…”

Section: Methodsmentioning

confidence: 99%

“…Agonist stimulated [ 35 S]GTP␥S (PerkinElmer) binding assay was carried out with SNC80 (Tocris Cookson, Bristol, U.K), deltorphin II (Sigma), and Met-enkephalin (Sigma) on brain membrane preparations as detailed in ref. 43.…”

Section: Methodsmentioning

confidence: 99%

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Knockin mice expressing fluorescent δ-opioid receptors uncover G protein-coupled receptor dynamics in vivo

Scherrer

Tryoen-Tóth

Filliol

et al. 2006

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

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The combination of fluorescent genetically encoded proteins with mouse engineering provides a fascinating means to study dynamic biological processes in mammals. At present, green fluorescent protein (GFP) mice were mainly developed to study gene expression patterns or cell morphology and migration. Here we used enhanced GFP (EGFP) to achieve functional imaging of a G proteincoupled receptor (GPCR) in vivo. We created mice where the ␦-opioid receptor (DOR) is replaced by an active DOR-EGFP fusion. Confocal imaging revealed detailed receptor neuroanatomy throughout the nervous system of knockin mice. Real-time imaging in primary neurons allowed dynamic visualization of drug-induced receptor trafficking. In DOR-EGFP animals, drug treatment triggered receptor endocytosis that correlated with the behavioral response. Mice with internalized receptors were insensitive to subsequent agonist administration, providing evidence that receptor sequestration limits drug efficacy in vivo. Direct receptor visualization in mice is a unique approach to receptor biology and drug design.behavioral desensitization ͉ green fluorescent protein ͉ neuroanatomy ͉ real-time imaging ͉ receptor internalization

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Knockin mice expressing fluorescent δ-opioid receptors uncover G protein-coupled receptor dynamics in vivo

Scherrer

Tryoen-Tóth

Filliol

et al. 2006

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

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226

275

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“…Mice were administered with 3, 5 or 10 mg/kg morphine or saline and analgesia tested using the tail immersion test as previously described (Scherrer et al, 2004;Contet et al, 2008). Briefly, 45 min following injection, the tail was immersed in a water bath set at 521C and tail withdrawal latencies were measured with a cut-off time of 10 s. Baseline responding was measured for 3 days before testing and just before the first injection.…”

Section: Behavioral Testingmentioning

confidence: 99%

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

Darcq

Befort

Koebel

et al. 2012

Neuropsychopharmacol

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It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo. Knockout mice for the rsk2 gene were tested for main morphine effects, including analgesia, tolerance to analgesia, locomotor activation, and sensitization to this effect, as well as morphine withdrawal. The deletion of RSK2 reduced acute morphine analgesia in the tail immersion test, indicating a role for this kinase in mu receptor-mediated nociceptive processing. All other morphine effects and adaptations to chronic morphine were unchanged. Because the mu opioid receptor and RSK2 both show high density in the habenula, we specifically downregulated RSK2 in this brain metastructure using an adeno-associated-virally mediated shRNA approach. Remarkably, morphine analgesia was significantly reduced, as observed in the total knockout animals. Together, these data indicate that RSK2 has a role in nociception, and strongly suggest that a mu opioid receptor-RSK2 signaling mechanism contributes to morphine analgesia at the level of habenula. This study opens novel perspectives for both our understanding of opioid analgesia, and the identification of signaling pathways operating in the habenular complex.

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“…Delta opioid receptor agonists administered peripherally either facilitate (Martinez et al, 1984;Pavone et al, 1990;Yang et al, 2003) or impair (Jutkiewicz et al, 2003;Martinez et al, 1984;Schulteis and Martinez, 1990;Ukai et al, 1997) avoidance or operant learning, while the preferential delta antagonist ICI 174,864 improves retrieval of avoidance conditioning in mice (Ilyutchenok and Dubrovina, 1995;Schulteis and Martinez, 1990). However, a major concern when using pharmacology is the possible cross-reactivity of delta agonists and antagonists at other opioid receptors (Hutcheson et al, 2001;Scherrer et al, 2004). Therefore, gene targeting represents a unique approach to address the specific role of each opioid receptor in vivo.…”

Section: Introductionmentioning

confidence: 99%

Impaired Hippocampus-Dependent and Facilitated Striatum-Dependent Behaviors in Mice Lacking the Delta Opioid Receptor

Merrer

Rezaï

Scherrer

et al. 2013

Neuropsychopharmacol

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Pharmacological data suggest that delta opioid receptors modulate learning and memory processes. In the present study, we investigated whether inactivation of the delta opioid receptor modifies hippocampus (HPC)-and striatum-dependent behaviors. We first assessed HPC-dependent learning in mice lacking the receptor (Oprd1 À / À mice) or wild-type (WT) mice treated with the delta opioid antagonist naltrindole using novel object recognition, and a dual-solution cross-maze task. Second, we subjected mutant animals to memory tests addressing striatum-dependent learning using a single-solution response cross-maze task and a motor skill-learning task. Genetic and pharmacological inactivation of delta opioid receptors reduced performance in HPC-dependent object place recognition. Place learning was also altered in Oprd1 À / À animals, whereas striatum-dependent response and procedural learning were facilitated. Third, we investigated the expression levels for a large set of genes involved in neurotransmission in both HPC and striatum of Oprd1 À / À mice. Gene expression was modified for several key genes that may contribute to alter hippocampal and striatal functions, and bias striatal output towards striatonigral activity. To test this hypothesis, we finally examined locomotor effects of dopamine receptor agonists. We found that Oprd1 À / À and naltrindole-treated WT mice were more sensitive to the stimulant locomotor effect of SKF-81297 (D1/D5), supporting the hypothesis of facilitated striatonigral output. These data suggest, for the first time, that delta receptor activity tonically inhibits striatal function, and demonstrate that delta opioid receptors modulate learning and memory performance by regulating the HPC/striatum balance.

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The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice

Cited by 73 publications

References 49 publications

Knockin mice expressing fluorescent δ-opioid receptors uncover G protein-coupled receptor dynamics in vivo

Knockin mice expressing fluorescent δ-opioid receptors uncover G protein-coupled receptor dynamics in vivo

RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia

Impaired Hippocampus-Dependent and Facilitated Striatum-Dependent Behaviors in Mice Lacking the Delta Opioid Receptor

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