Opioid regulation of hypothalamic neurons

阿片类药物对下丘脑神经元的调节

基本信息

批准号：
8702132
负责人：
SHANE T HENTGES
金额：
$ 31.41万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702132
关键词：
Absence of pain sensation Accounting Acute Affect Agonist Amino Acids Biological Assay Biological Models Brain Cells Chronic Clinical Conflict (Psychology)Data Development Dose Eating Endorphins Exposure to Goals Hypothalamic structure Image Life Measures Mediating Neurons Nucleus Accumbens Opioid Opioid Receptor Pain Pathway interactions Peptides Phosphorylation Preparation Presynaptic Receptors Presynaptic Terminals Pro-Opiomelanocortin Property Receptor Signaling Recycling Regulation Reporting Research Resistance Rewards Site Slice Structure of nucleus infundibularis hypothalami Structure of terminal stria nuclei of preoptic region Testing Therapeutic Ventral Tegmental Area Whole-Cell Recordings Work cellular imaging chronic pain desensitization endogenous opioids enhanced green fluorescent protein insight midbrain central gray substance mu opioid receptors opioid abuse optogenetics postsynaptic presynaptic prevent receptor receptor function receptor internalization receptor sensitivity relating to nervous system research study reward circuitry trafficking treatment duration

项目摘要

DESCRIPTION (provided by applicant): Opioid receptor agonists are highly effective at producing analgesia, but their clinical use is hindered by the development of tolerance and high abuse liability resulting from activation of the neural reward circuitry. Therefore, understanding how opioids regulate reward circuits and how opioid receptor signaling changes with opioid exposure are key steps towards overcoming current clinical limitations of opioid therapy. One important reward pathway that releases and responds to opioids includes the hypothalamic proopiomelanocortin (POMC) neurons. Recent data show that POMC neurons are regulated by opioids acting on POMC neurons and also by opioids acting on terminals presynaptic to POMC neurons. Interestingly, while postsynaptic mu opioid receptors on POMC neurons undergo desensitization within minutes, presynaptic mu opioid receptors that mediate the inhibition of transmitter release do not readily desensitize. The goals of the present proposal are to 1) determine the mechanisms underlying the presynaptic resistance to desensitization and 2) to determine the consequence of differential pre- and postsynaptic opioid receptor regulation. These goals will be achieved using electrophysiologic, optogenetic and imaging approaches in brain slices. The results may provide insight into ways to prevent postsynaptic receptor desensitization and will thoroughly define how opioids affect neuron activity in a reward circuit via pre- and postsynaptic receptors during acute and chronic exposure to opioids.

描述（由申请人提供）：阿片受体激动剂在产生镇痛方面非常有效，但是由于神经奖励电路的激活而导致的耐受性和高滥用责任的发展阻碍了它们的临床用途。因此，了解阿片类药物如何调节奖励电路以及阿片受体信号如何随着阿片类药物的暴露而变化是克服当前阿片类药物治疗的临床局限性的关键步骤。释放和反应阿片类药物的一项重要奖励途径包括下丘脑propiomelananocortin（POMC）神经元。最近的数据表明，POMC神经元受作用于POMC神经元的阿片类药物以及作用于POMC神经元前末端的阿片类药物来调节。有趣的是，尽管POMC神经元上的突触后MU阿片类受体会在几分钟内经历脱敏，但介导抑制发射机释放的抑制作用的突触前MU阿片受体并不能容易脱敏。本提案的目标是1）确定突触前抗脱敏性的机制，以及2）确定差异前和突触后阿片受体调节的后果。这些目标将使用脑切片中的电生理，光遗传学和成像方法来实现。结果可能会提供有关预防突触后受体脱敏方法的洞察力，并将在急性和长期暴露于阿片类药物期间通过突触前和突触后受体在奖励电路中如何影响阿片类药物的神经元活性。