Cellular, synaptic, and network adaptations of MCL addiction and motivation circuits (NAc, VTA, PAG) with chronic pain and opioid exposure

MCL 成瘾和动机回路（NAc、VTA、PAG）与慢性疼痛和阿片类药物暴露的细胞、突触和网络适应

• 批准号: 10440295
• 负责人: DALTON JAMES SURMEIER
• 金额: $ 31.14万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440295
• 关键词: Affect; Amygdaloid structure; Anatomy; Attenuated; Behavior; Behavioral; Brain; Cells; Collaborations; Complement; Cues; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Drug abuse; Electrophysiology (science); Epidemic; Excitatory Synapse; Extinction (Psychology); Goals; Hippocampus (Brain); Human; Label; Lesion; Link; Medial; Modeling; Modernization; Molecular; Morphine; Motivation; Mus; Neurobiology; Neurons; Nociception; Nucleus Accumbens; Opioid; Optics; Pain; Pharmaceutical Preparations; Physiological; Play; Prefrontal Cortex; Property; Protocols documentation; Psychological reinforcement; Rewards; Rodent; Role; Schedule; Self Administration; Shapes; Signal Transduction; Slice; Source; Synapses; Testing; Time; Training; Transgenic Mice; Ventral Tegmental Area; Withdrawal; Work; addiction; addiction liability; attenuation; chronic back pain; chronic pain; chronic pain patient; disability; dopaminergic neuron; drug seeking behavior; experimental study; insight; mouse model; nerve injury; novel therapeutics; opioid abuse; opioid exposure; optogenetics; pain behavior; paraventricular nucleus; prescription opioid; spared nerve; synergism; tool

Chronic pain is the top source of disability in the U.S. and is commonly treated with opiates. Many chronic pain patients given prescription opiates for treatment struggle with addiction and the abuse of opioids has reached epidemic proportions in the U.S. The neurobiological basis for the connection between chronic pain and opioid abuse is uncertain. However, recent work has shown that chronic pain is shaped by the same mesolimbic circuitry underlying drug addiction. The ventral tegmental area (VTA) and nucleus accumbens (NAc) appears to be critical hubs of this circuitry. Their role in drug addiction is well-established. What is new is that they also play key roles in chronic pain. We have shown that in the rodent spared nerve injury (SNI) model of chronic pain there are cell-specific and region-specific adaptations in the NAc that include both intrinsic and synaptic changes. These changes were causally linked to pain behavior and alterations in the activity of dopaminergic neurons in the VTA. Although there are clear effects of opioids on the VTA and NAc, how opioids shape SNI-induced adaptations in the NAc is completely unexplored. Moreover, it is unclear how chronic pain modifies the addictive potential of opioids. In Project 2, our over-arching goal is to fill these gaps in our understanding. To this end, an array of modern behavioral, anatomical, physiological and molecular approaches will be used in mouse models to achieve four specific aims: Specific Aim 1: To determine whether morphine reinforcement and seeking behavior is enhanced in SNI mice trained to self-administer morphine. Our working hypothesis is that SNI will increase the reinforcing efficacy of morphine and drug seeking behavior. Specific Aim 2: To determine whether SNI differentially affects VTA DA neurons innervating the medial shell and core of the NAc and whether these effects are modulated by morphine self-administration (MSA). Our working model is that VTA regions innervating the msNAc and cNAc are non-overlapping and respond in largely opposing ways to SNI. Moreover, we hypothesize that short-term MSA will diminish SNI-induced adaptations. Specific Aim 3: To determine whether short-term (5d) morphine self-administration alters SNI-induced adaptations in specific NAc circuits. Our working hypothesis is that MSA shortly after SNI will dampen ascending nociceptive signaling and attenuate alterations in the activity of VTA, resulting in only modest adaptations in msNAc/cNAc circuits. Specific Aim 4: To determine whether long-term (14 d) morphine self- administration and withdrawal alters SNI induced adaptations in specific NAc circuits. Our working hypothesis is that with time the beneficial effects of morphine on VTA and NAc circuits will wane, leading to augmentation of SNI-induced adaptations in NAc circuits, resulting in enhanced morphine reward and drug seeking. The studies outlined for these four aims should provide fundamental new insights into the mechanisms by which chronic pain increases the potential for addiction to opioids, like morphine, and in so doing point to novel therapies. Moreover, these aims complement those of Projects 1, 3 and 4, creating an opportunity for synergy.

慢性疼痛是美国残疾的主要来源，通常用阿片类药物治疗。许多慢性疼痛患者 为治疗提供处方阿片类药物，与成瘾作斗争，滥用阿片类药物已成为流行病 慢性疼痛和阿片类药物滥用之间联系的神经生物学基础是 不确定然而，最近的研究表明，慢性疼痛是由同样的中脑边缘回路形成的， 毒瘾腹侧被盖区（VTA）和延髓核（NAc）似乎是这一过程的关键枢纽。 电路他们在吸毒成瘾方面的作用是众所周知的。新的是，它们在慢性疼痛中也起着关键作用。我们 已经表明，在慢性疼痛的啮齿动物备用神经损伤（SNI）模型中，存在细胞特异性和区域特异性的 NAc中的适应包括内在和突触变化。这些变化与疼痛有因果关系 行为和腹侧被盖区多巴胺能神经元活性的改变。虽然阿片类药物有明显的作用 在VTA和NAc上，阿片类药物如何在NAc中形成SNI诱导的适应性完全未被探索。而且是 尚不清楚慢性疼痛如何改变阿片类药物的成瘾潜力。在项目2中，我们的超额目标是填补这些 我们理解的差距。为此，一系列现代行为、解剖、生理和分子技术 方法将用于小鼠模型，以实现四个具体目标：具体目标1：确定吗啡是否 强化和寻求行为在训练自我施用吗啡的SNI小鼠中增强。我们的工作假设 SNI将增加吗啡的强化功效和药物寻求行为。具体目标2：确定 SNI是否差异性地影响支配NAc内侧壳和核心的VTA DA神经元，以及这些神经元是否 通过吗啡自我给药（MSA）调节效应。我们的工作模型是，VTA区域支配的 msNAc和cNAc是不重叠的，并且以很大程度上相反的方式响应SNI。此外，我们假设， 短期的MSA将减少SNI诱导的适应。具体目标3：确定短期（5天）吗啡 自我给药改变了特定NAc回路中SNI诱导的适应。我们的工作假设是， 在SNI后，将抑制上行伤害性信号传导并减弱VTA活性的改变， msNAc/cNAc电路中的适度调整。具体目标4：确定长期（14天）吗啡自我- 给药和停药改变了SNI诱导的特定NAc回路的适应。我们的假设是 随着时间的推移，吗啡对VTA和NAc回路的有益作用将减弱，导致SNI诱导的 NAc回路的适应，导致吗啡奖励和药物寻求的增强。针对这四项研究的概述 目的应该提供基本的新见解的机制，慢性疼痛增加的潜力， 成瘾阿片类药物，如吗啡，并在这样做的点，新的疗法。此外，这些目标补充了 项目1、3和4，创造协同作用的机会。