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：
9118937
负责人：
SHANE T HENTGES
金额：
$ 31.47万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9118937
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 chronic pain desensitization endogenous opioids enhanced green fluorescent protein insight live cell imaging 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，但其临床使用因神经奖赏回路激活导致的耐受性和高滥用倾向的发展而受到阻碍。因此，了解阿片类药物如何调节奖赏回路以及阿片类药物受体信号如何随着阿片类药物暴露而变化，是克服阿片类药物治疗当前临床局限性的关键步骤。释放阿片类药物并对其做出反应的一种重要奖励途径包括下丘脑阿片黑皮质素原 (POMC) 神经元。最近的数据表明，POMC 神经元受到作用于 POMC 神经元的阿片类药物以及作用于 POMC 神经元突触前末端的阿片类药物的调节。有趣的是，虽然 POMC 神经元上的突触后 mu 阿片受体在几分钟内经历脱敏，但介导递质释放抑制的突触前 mu 阿片受体却不容易脱敏。本提案的目标是：1）确定突触前对脱敏的抵抗的机制；2）确定突触前和突触后阿片受体调节差异的结果。这些目标将通过脑切片中的电生理学、光遗传学和成像方法来实现。研究结果可能为防止突触后受体脱敏的方法提供深入见解，并将彻底定义阿片类药物在急性和慢性暴露于阿片类药物期间如何通过突触前和突触后受体影响奖赏回路中的神经元活动。