THERAPEUTIC PROFILES OF OPIOID DELTA RECEPTORS--NEW MODALITIES
阿片类药物 Delta 受体的治疗概况——新模式
基本信息
- 批准号:6300720
- 负责人:
- 金额:$ 10.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-04-01 至 2001-03-31
- 项目状态:已结题
- 来源:
- 关键词:analgesics cell line cell type dorsal root drug addiction drug design /synthesis /production drug screening /evaluation fluorescence microscopy laboratory rat narcotic antagonists neuropeptide receptor neuropeptides oligonucleotides opioid receptor peptide analog pharmacokinetics receptor expression receptor sensitivity
项目摘要
The aims of this project are based on three hypothesis.
Hypothesis 1 is that the opioid delta receptor may exist as
subtypes. An antisense strategy will be employed in NG 108-15
cells, in primary DRG cultures and in an antinociceptive model
in vivo. Antisense oligodeoxynucleotide (ODN) "knock-down" of
delta receptors in NG108-15 cells will be studied using ODNs
directed at the DOR-1 clone and at a conserved sequence in the
opioid mu, delta and kappa receptors (conserved opioid receptor;
COR). Cellular uptake and ODN translocation, time-course,
concentration-dependence and inhibition of the delta receptor
expression will be determined with fluorescence microscopy and
radioligand binding; control ODN sequences will be emphasized.
In DRG cultures DOR or COR antisense ODN will be used to evaluate
ODN uptake and morphological distribution and to validate the DOR
ODN selectivity against delta mu and kappa receptors. In rats,
DOR/COR ODNs will be used to elucidate the distribution of spinal
ODNs and "knock-down" of opioid receptors and possible
differential sensitivity of putative delta subtype selective
agonists (but not mu or kappa agonists), to DOR-1 antisense ODN
effects as well as time-course and recovery of the
antinociceptive effect. Hypothesis 2 is that activation of
supraspinal opioid delta receptors will produce antinociception
not necessarily dependent on the descending pathway characterized
for opioid mu receptor agonists. Localized microinjection of
opioid subtype selective agonists and antagonists into selected
supraspinal loci will be employed to establish receptor selective
antinociceptive activity. The involvement of descending pathways
following activation of confirmed supraspinal delta
antinociception will be studied by examining suppression of
nociceptive induced behavior and c-FOS expression in the spinal
cord in control rats, or in animals with lesions of the
dorsolateral funiculus (DLF). Hypothesis 3 is that activation
of both supraspinal and spinal opioid delta receptors will result
in a synergistic antinociceptive effect. Analysis of
antinociception elicited by supraspinal/spinal co-administration
of subtype-selective agonists in a fixed-ratio paradigm with
isobolographic methods will be used. These experiments should
yield significant new information about the role of the delta
receptor in nociception and the bossibility of subtypes of this
receptor in vitro and in vivo.
这个项目的目标是基于三个假设。
假设1阿片受体可能以
子类型。在NG 108-15中将采用反义策略
在原代培养的DRG和抗伤害性模型中的细胞
在活体内。反义寡核苷酸(ODN)“敲除”
将使用ODN研究NG108-15细胞中的Delta受体
针对DOR-1克隆和
阿片受体(保守的阿片受体;
COR)。细胞摄取和ODN转位,时间进程,
β受体的浓度依赖性和抑制作用
表达将用荧光显微镜和
放射性配基结合;将重点介绍控制ODN序列。
在DRG培养中,将使用DOR或COR反义ODN来评估
ODN摄取与形态分布及DOR的验证
ODN对Delta Mu和Kappa受体的选择性。在老鼠身上,
DOR/COR ODN将用于阐明脊髓的分布
ODN与阿片受体的“击倒”及其可能
假定的三角洲亚型选择性的差异敏感性
DOR-1反义ODN激动剂(但不是Mu或Kappa激动剂)
的影响以及时间进程和恢复
抗伤害作用。假设2是激活
脊髓上阿片受体将产生抗伤害作用
不一定依赖于所描述的下行路径
用于阿片类u受体激动剂。局部微量注射
阿片亚型选择性激动剂和拮抗剂入选
将利用脊髓上的基因座来建立选择性受体
抗伤害性作用。下行通路的参与
在确认的棘上三角区激活后
抗伤害性作用的研究将通过检查抑制
脊髓伤害性行为和c-fos的表达
对照大鼠的脊髓,或有脊髓损伤的动物的脊髓
背外侧索(DLF)。假设3是激活
将导致脊髓上和脊髓阿片三角洲受体的
具有协同的抗伤害作用。分析
脊柱上/脊柱联合给药引起的抗伤害效应
亚型选择性激动剂在固定比例的范例中
将使用等同相学方法。这些实验应该
提供了关于三角洲作用的重要新信息
伤害性感受中的受体及其亚型的易感性
体外和体内受体。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Frank Porreca的其他文献
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{{ truncateString('Frank Porreca', 18)}}的其他基金
The Center of Excellence in Addiction Studies (CEAS)
成瘾研究卓越中心 (CEAS)
- 批准号:
10626079 - 财政年份:2021
- 资助金额:
$ 10.45万 - 项目类别:
The Center of Excellence in Addiction Studies (CEAS)
成瘾研究卓越中心 (CEAS)
- 批准号:
10469424 - 财政年份:2021
- 资助金额:
$ 10.45万 - 项目类别:
The Center of Excellence in Addiction Studies (CEAS)
成瘾研究卓越中心 (CEAS)
- 批准号:
10270346 - 财政年份:2021
- 资助金额:
$ 10.45万 - 项目类别:
New Modalities for the Treatment of Pain and Drug Abuse-Administrative Core
治疗疼痛和药物滥用的新方式——管理核心
- 批准号:
9073234 - 财政年份:2017
- 资助金额:
$ 10.45万 - 项目类别:
Cortical opioid dysfunction in chronic pain
慢性疼痛中的皮质阿片类药物功能障碍
- 批准号:
9479906 - 财政年份:2016
- 资助金额:
$ 10.45万 - 项目类别:
Cortical opioid dysfunction in chronic pain
慢性疼痛中的皮质阿片类药物功能障碍
- 批准号:
9259931 - 财政年份:2016
- 资助金额:
$ 10.45万 - 项目类别:
Brain reward circuits and relief of ongoing pain
大脑奖励回路和缓解持续疼痛
- 批准号:
8431853 - 财政年份:2013
- 资助金额:
$ 10.45万 - 项目类别:
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