The contribution of the hippocampus to learned opiate tolerance

海马体对习得阿片耐受性的贡献

基本信息

批准号：
10586097
负责人：
Brian J Wiltgen
金额：
$ 19.43万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10586097
关键词：
Absence of pain sensation Affect Amygdaloid structure Analgesics Animals Area Association Learning Attenuated Behavioral Biological Assay Brain Cells Chronic Clinical Cocaine Cues Dangerousness Data Dependence Development Dose Environment Exhibits FOS gene Goals Hippocampus Infusion procedures Label Learning Light Mediating Memory Methadone Methods Modernization Morphine Mus Neurons Neurosciences Nucleus Accumbens Opioid Opioid Receptor Opioid agonist Opsin Overdose Pain Pharmaceutical Preparations Pharmacodynamics Play Proteins Reporter Reporter Genes Research Role Signal Pathway Specificity Techniques Testing Training Transgenic Organisms United States Viral Vector Virus Work addiction clinically relevant conditioned fear cost estimate desensitization drug abuse prevention drug efficacy experimental study fear memory memory retrieval morphine tolerance neural circuit novel opiate tolerance opioid use optogenetics pain inhibition pain sensitivity prevent receptor recycling response side effect spatial memory synthetic opioid tool

项目摘要

Project Summary The utility of opiates for treating pain is limited by the development of tolerance, a phenomenon that can lead to dose- escalation and an increased liability for dangerous side effects like dependence and overdose. Interestingly, environmental cues that are paired with opiates can dramatically influence tolerance. Specifically, animals that receive morphine in a particular context exhibit analgesic tolerance that can be eliminated by simply administering the drug in a new environment. The cellular and circuit mechanisms underlying this associative form of tolerance have not been well characterized. However, they are highly relevant clinically as many overdoses occur when addicts take large amounts of opiates in a new place. In this application, we propose to dissect the circuitry underlying associate morphine tolerance using modern behavioral neuroscience tools. Specifically, we will combine optogenetic techniques with transgenic reporter mice to identify the specific neural circuits and cells that mediate associative tolerance. Our central hypothesis is that context-specific representations in the hippocampus become associated with opiate use and produce a compensatory response in the amygdala that prevents the inhibition of pain. To test this idea, we will express light sensitive opsins in the specific neurons that are active during the expression of associative morphine tolerance. We predict that silencing these cells will prevent tolerance in a morphine-paired context. Stimulating these cells, in contrast, should induce tolerance in a novel environment that has never been paired with morphine. A similar strategy has been used to identify and manipulate neurons that encode fear memories in the amygdala, spatial memories in the hippocampus, cocaine memories in the nucleus accumbens and many others forms of memory. However, to our knowledge, this approach has never been applied to associative morphine tolerance. We believe that doing so will lead to significant advances like it has for other forms of learning and memory.

项目概要阿片类药物治疗疼痛的效用受到耐受性发展的限制，这种现象可能导致剂量- 升级以及对危险副作用（如依赖性和过量）的责任增加。有趣的是，与阿片类药物相结合的环境因素可以极大地影响耐受性。具体来说，动物接受吗啡在特定情况下表现出镇痛耐受性，可以通过简单地以药物形式给药来消除这种耐受性。新环境。这种关联形式的耐受性背后的细胞和电路机制尚未得到很好的了解特点。然而，它们在临床上具有高度相关性，因为当成瘾者服用大量药物时，会发生许多药物过量的情况。在新地方吸鸦片。在此应用中，我们建议剖析与吗啡耐受相关的潜在电路使用现代行为神经科学工具。具体来说，我们将光遗传学技术与转基因技术相结合报告小鼠来识别介导联想耐受的特定神经回路和细胞。我们的中心假设海马体中特定环境的表征与阿片类药物的使用相关并产生杏仁核的代偿反应可以防止疼痛的抑制。为了测试这个想法，我们将表达光特定神经元中的敏感视蛋白在相关吗啡耐受表达期间活跃。我们预测沉默这些细胞将阻止吗啡配对环境中的耐受性。相反，刺激这些细胞，应该在从未与吗啡配对的新环境中诱导耐受性。类似的策略已经用于识别和操纵编码杏仁核中的恐惧记忆、大脑中的空间记忆的神经元海马体、伏隔核中的可卡因记忆以及许多其他形式的记忆。然而，对于我们的据了解，这种方法从未应用于联想吗啡耐受。我们相信这样做会导致像其他形式的学习和记忆一样取得重大进展。