权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MIXED NOP/MU COMPOUNDS AND THE INVOLVEMENT OF THEIR RECEPTORS IN ANALGESIA

混合 NOP/MU 化合物及其受体在镇痛中的作用

基本信息

批准号：
10199982
负责人：
LAWRENCE R TOLL
金额：
$ 45.24万
依托单位：
FLORIDA ATLANTIC UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199982
关键词：
Absence of pain sensation Acute Acute Pain Affective Afferent Neurons Agonist Analgesics Anatomy Animals Anterior Attenuated Back Behavior Behavioral Brain Brain region C-terminal Cells Chimeric Proteins Chronic Coupled Crystallization Development Dimerization Down-Regulation Drug abuse Emotional Family Fc Receptor Gender Grant Green Fluorescent Proteins Histocytochemistry Hyperalgesia Injections Investigation Knock-in Mouse Laboratories Ligands Location Mechanics Mediating Messenger RNA Methods Microinjections Modality Mus Neurons Neuropathy Nociception Opioid Opioid Analgesics Opioid Receptor Pain Pathway interactions Peripheral Pharmaceutical Preparations Pharmacology Property Receptor Activation Receptor Down-Regulation Research Role Sensory Skin Spinal Spinal Cord Spinal Ganglia Spinal nerve structure Structure System Tactile Testing Thalamic structure Touch sensation allodynia animal pain brain pathway chronic neuropathic pain chronic pain chronic painful condition cingulate cortex delta receptors enhanced green fluorescent protein experimental study inflammatory pain member mu opioid receptors mu receptors neural circuit novel pain processing painful neuropathy postsynaptic prevent protein expression protein kinase C gamma receptor receptor function response sensory system small molecule somatosensory tool

项目摘要

The NOP receptor, the fourth member of the opioid receptor family, has been the target of investigation since its discovery in 1993, with respect to pharmacology, anatomy, and behaviors elicited by agonists and antagonists. Despite considerable research efforts, the lack of suitable receptor antibodies has prevented the appropriate interpretation of many studies pertaining to the details of receptor location, internalization, and dimerization. In order to test hypotheses pertaining to NOP receptor function, Dr. Brigitte Kieffer and colleagues have generated knock-in mice that carry green fluorescent protein (eGFP) coupled to the NOP receptor. Similar GFP-tagged delta receptor and mCherry-tagged mu receptor knock-in mice have proven very useful in understanding the relationship among anatomy, cellular localization, and function of delta and mu opioid receptors. Like the mu receptor, NOP receptors are found in very high numbers in all of the pain-related brain regions, including PAG, RVM, MHb, thalamus, etc. However, NOP receptors are unlike the other members of the opiate receptor family in that NOP receptor agonists block opiate analgesia when administered i.c.v. while having antinociceptive activity when administered intrathecally. In addition, NOP receptor agonists appear to be more effective rather than less effective in chronic pain states. This is surprising since NOP receptor mRNA decreases in DRG and anterior cingulate cortex (ACC) and NOP receptors decrease in certain spinal cord laminae in spinal nerve ligated mice. Using NOP-eGFP(+/+) mice, immunohistochemical experiments will be carried out to better understand the circuitry and the cellular localization in brain, spinal cord, and DRG that leads to these unusual properties of N/OFQ and other NOP receptor agonists. These will be correlated with behavioral experiments subsequent to microinjections into specific brain regions to understand how NOP receptor activation modulates the sensory as well as the affective component of pain. Specific Aim 1 will carefully examine the location of NOP-eGFP receptors in DRG as well as determine the pain modalities (heat, cold, touch) attenuated by systemic administration of NOP agonists and antagonists and determine how these parameters change during chronic neuropathic and inflammatory pain. Specific Aim 2 will examine spinal cord NOP-eGFP expression as well as characterize spinal projections both to the brain and to the periphery. These results will be compared with the effects of NOP agonists on different pain modalities after intrathecal administration in sham and neuropathic mice. Specific Aim 3 will examine neuropathic pain-induced changes in NOP-eGFP receptor levels in brain with particular emphasis on regions involved in the sensory (PAG) and affective (ACC) components of pain. Direct injections of NOP receptor agonists and antagonists into these brain regions will be used to better understand the NOP receptor-related circuitry that modulates thermal, tactile, and emotional pain through these brain regions. These experiments will clearly identify the role of NOP receptors in acute and chronic thermal and tactile pain, allodynia and hyperalgesia.

NOP受体是阿片受体家族的第四个成员，一直是研究的目标

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.

DOI：
10.1111/bph.13854
发表时间：
2017-08
期刊：
British journal of pharmacology
影响因子：
7.3
作者：
Spetea M;Eans SO;Ganno ML;Lantero A;Mairegger M;Toll L;Schmidhammer H;McLaughlin JP
通讯作者：
McLaughlin JP

Structural determinants of opioid and NOP receptor activity in derivatives of buprenorphine.