Pharmacology of Kappa Opioid Receptor
Kappa 阿片受体的药理学
基本信息
- 批准号:10400320
- 负责人:
- 金额:$ 15.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:ADRBK2 geneAbnormal coordinationAbsence of pain sensationAcetic AcidsAdenylate CyclaseAdministrative SupplementAgonistAnalgesicsAntipruritic EffectAntipruriticsArr2ArrestinsAttenuatedAwardBehaviorC-terminalClinicalDevelopmentDiuresisEstrogen ReplacementsExhibitsFemaleFundingFutureG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGonadal Steroid HormonesInvestigationKnock-outKnockout MiceLeadLiteratureMAP Kinase GeneMAPK3 geneMAPK4 geneMediatingMenstrual cycleMotorMotor ActivityMusMutationOpioid ReceptorOpioid agonistOrchiectomyOvariectomyParentsPathway interactionsPharmacologyPhasePhenotypePhosphorylationPlayPopulationPotassium ChannelProteinsPublishingReceptor ActivationReceptor SignalingRegulationReportingRhodopsinRoleSedation procedureSex DifferencesSideSignal TransductionTestingTestosteroneTherapeutic EffectTimeVentilatory DepressionWaterWorkbasebehavioral phenotypingbehavioral responsebeta-arrestinclinical developmentdesensitizationdysphoriaexperimental studyfemale sex hormonein vivokappa opioid receptorsmalep38 Mitogen Activated Protein Kinasereceptorrecruitsexside effect
项目摘要
Kappa opioid receptor (KOR), one of the three opioid receptors, is a G protein-coupled receptor (GPCR). KOR
agonists produce analgesic and anti-pruritic effects, but their development for clinical use has been limited by
side effects, most importantly dysphoric and psychotomimetic effects. KOR activation results in G protein- and
-arrestins-dependent signaling as well as -arrestins-mediated KOR desensitization and internalization. It is
thought that biased KOR agonists preferentially activating G protein-dependent pathways may produce
analgesic and anti-pruritic effects with fewer side effects. For Specific Aim 3.1 of the parent funded award, we
have been examining the roles of agonist-promoted phosphorylation in KOR-mediated behavioral responses
by generating and characterizing mice harboring S356A/T357A/T363A/S369A mutations in the KOR (K4A).
K4A mice do not undergo agonist-induced receptor phosphorylation and thus do not recruit -arrestins. For
comparison, we examined KOR-mediated behaviors in -arrestin2 (-arr2) knockout (KO) mice. We found that
-arr2 deletion in mice enhanced anti-scratch effects produced by the selective KOR agonist U50,488H in
males, but not in females. In contrast, -arr2 deletion did not affect U50,488H-induced aversion in either male
or female mice. Thus, whether -arr2 deletion has sex-specific effects depends on the behavior examined. To
our knowledge, this is the first demonstration that -arr2 deletion has different effects in females vs. males on
GPCR-mediated behaviors. Published studies on -arr2 KO mice have been performed in males or a mixed
population of males and females. Thus, studies on female -arr2 KO mice to define possible sex differences
are warranted. For this administrative supplement, we propose the following two specific aims. For specific aim
1, we will examine if there are sex differences in the effect of -arr2 deletion on the KOR-mediated analgesic
effect, locomotor activity and tolerance. Experiments will be performed using U50,488H in male and female WT
and -arr2 KO mice. The acetic acid writhing test will be used to assess the analgesic effect and inhibition of
novelty-induced locomotor activity will be examined. Tolerance will be investigated in the anti-pruritic and
analgesic tests following repeated U50,488H treatment. For specific aim 2, we will investigate if sex hormones
play a role in the sex differences in effects of -arr2 deletion on U50,488H-induced behaviors. We will examine
if ovariectomy (OVX) and orchidectomy (ORX) changes U50,488H-induced behavioral phenotypes in -arr2
KO mice. If so, in the future whether estrogen replacement in OVX mice and testosterone replacement in ORX
mice restore the phenotypes will be examined. This is the first comprehensive investigation on the roles of -
arr2 in GPCR-mediated behaviors in both males and females. Different roles of -arr2 in males vs. females in
KOR-mediated behaviors have clinical implications in that -arr2 signaling-mediated behaviors may exhibit sex
differences following KOR activation. If female sex hormones are involved in the sex differences, KOR
signaling and regulation in females may vary in different stages of a menstrual cycle.
κ阿片受体(Kappa opioid receptor,KOR)是G蛋白偶联受体(G protein-coupled receptor,GPCR),是三大阿片受体之一。KOR
激动剂产生镇痛和抗过敏作用,但它们的临床应用发展受到以下因素的限制:
副作用,最重要的是烦躁不安和拟精神病作用。KOR激活导致G蛋白-和
β-抑制蛋白依赖性信号传导以及β-抑制蛋白介导的KOR脱敏和内化。是
我认为偏向性KOR激动剂优先激活G蛋白依赖性通路可能会产生
具有镇痛、抗炎作用,副作用少。对于家长资助奖的具体目标3.1,我们
一直在研究激动剂促进的磷酸化在KOR介导的行为反应中的作用
通过产生和表征在KOR(K4 A)中携带S356 A/T357 A/T363 A/S369 A突变的小鼠。
K4 A小鼠不经历激动剂诱导的受体磷酸化,因此不募集β-arrestins。为
作为比较,我们在β-arr 2(β-arr 2)敲除(KO)小鼠中检查了KOR介导的行为。我们发现
在小鼠中,E-arr 2缺失增强了选择性KOR激动剂U 50,488 H在小鼠中产生的抗划痕作用。
男性,而不是女性。相反,在两个雄性中,U 50,488 H诱导的厌恶感不受U 50,488 H诱导的厌恶感的影响
或雌性小鼠。因此,是否有性别特异性的影响取决于检查的行为。到
据我们所知,这是第一次证明,在女性和男性中,
GPCR介导的行为。已经在雄性或混合小鼠中进行了已发表的关于p53-arr 2 KO小鼠的研究。
男性和女性的人口。因此,对雌性ARR-ARR 2基因敲除小鼠进行研究以确定可能的性别差异,
都是正当的对于这一行政补充,我们提出以下两个具体目标。为特定目的
1,我们将检查是否有性别差异,在影响的kor-arr 2缺失对KOR介导的镇痛
影响,自发活动和耐受性。将使用U 50,488 H在雄性和雌性WT中进行实验
和p53-arr 2 KO小鼠。醋酸扭体试验将用于评估镇痛作用和抑制
将检查新奇诱导的运动活动。将研究抗过敏药物的耐受性,
重复U 50,488 H治疗后的镇痛试验。对于具体目标2,我们将研究性激素是否
在U 50,488 H诱导的行为中,E-arr 2基因缺失对行为的影响存在性别差异。我们将研究
如果卵巢切除术(OVX)和睾丸切除术(ORX)改变了U 50,488 H诱导的ARR 2的行为表型,
KO小鼠。如果是这样的话,将来是否在OVX小鼠中进行雌激素替代和在ORX小鼠中进行睾酮替代
将检查恢复表型的小鼠。这是第一次全面调查的作用,
arr 2在男性和女性的GPCR介导的行为。不同的角色,男性与女性的arr 2在
KOR介导的行为具有临床意义,因为KOR-arr 2信号介导的行为可能表现出性别差异。
KOR激活后的差异。如果女性性激素参与了性别差异,KOR
女性的信号传导和调节在月经周期的不同阶段可能不同。
项目成果
期刊论文数量(0)
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LEE-YUAN LIU-CHEN其他文献
LEE-YUAN LIU-CHEN的其他文献
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{{ truncateString('LEE-YUAN LIU-CHEN', 18)}}的其他基金
Kappa Opioid Receptor in Paraventricular Nucleus of Thalamus
丘脑室旁核中的 Kappa 阿片受体
- 批准号:
10659960 - 财政年份:2023
- 资助金额:
$ 15.85万 - 项目类别:
Generation of knockin mice expressing KOPR conjugated with a fluorescent protein
表达与荧光蛋白缀合的 KOPR 的敲入小鼠的产生
- 批准号:
8623020 - 财政年份:2014
- 资助金额:
$ 15.85万 - 项目类别:
Generation of knockin mice expressing KOPR conjugated with a fluorescent protein
表达与荧光蛋白缀合的 KOPR 的敲入小鼠的产生
- 批准号:
8836513 - 财政年份:2014
- 资助金额:
$ 15.85万 - 项目类别:
Cellular Pharmacology of Kappa Opioid Receptor
Kappa 阿片受体的细胞药理学
- 批准号:
7232651 - 财政年份:2004
- 资助金额:
$ 15.85万 - 项目类别:
Cellular Pharmacology of Kappa Opioid Receptor
Kappa 阿片受体的细胞药理学
- 批准号:
7064864 - 财政年份:2004
- 资助金额:
$ 15.85万 - 项目类别: