The role of the nigrothalamic pathway in opioid-driven behaviors

黑丘脑通路在阿片类药物驱动行为中的作用

• 批准号: 10730268
• 负责人: Ewa Joanna Galaj
• 金额: $ 40.5万
• 依托单位: COLGATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730268
• 关键词: Ablation; Absence of pain sensation; Address; Affect; Analgesics; Attenuated; Behavior; Biological Assay; Brain region; CASP3 gene; Clinical; Data; Disinhibition; Female; General Population; Genetic; Glutamates; Goals; Helping to End Addiction Long-term; Heroin; In Situ Hybridization; Interneurons; Knowledge; Lesion; Link; Measures; Mediating; Midbrain structure; Mus; Neurobiology; Neurons; Neurotoxins; Nociception; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pathway interactions; Persons; Pharmaceutical Preparations; Play; Public Health; Relapse; Reporting; Research; Rewards; Role; Saline; Self Administration; Sex Differences; Substantia nigra structure; Tail; Techniques; Testing; Thalamic structure; Time; United States National Institutes of Health; Universities; Ventral Tegmental Area; Virus; Visualization; Woman; abuse liability; addiction; antagonist; career preparation; chronic pain; clinically relevant; design; dopaminergic neuron; drug reward; experience; experimental study; gamma-Aminobutyric Acid; heroin use; improved; insight; mRNA Expression; male; men; mu opioid receptors; neural; neuromechanism; neuronal circuitry; new therapeutic target; novel; opioid epidemic; opioid use; optogenetics; pharmacologic; postsynaptic; prescription opioid; response; treatment strategy; undergraduate student

Project Summary Chronic pain represents a significant clinical problem, affecting up to 20% of the general population. Over- prescription of opioid analgesics has led to the current opioid epidemic as these medications carry high abuse liability due to the rewarding effects they produce. Thus, to improve treatment strategies for pain and opioid dependence, it is necessary to uncover the neural mechanisms underlying these debilitating conditions. Opioid reward has traditionally been thought to involve disinhibition of midbrain dopamine neurons by local GABA interneurons. However, we recently found that GABA neurons with high expression of mu opioid receptors in the substantia nigra pars reticulata (SNr), a brain region largely ignored in the reward and addiction fields, play a critical role in heroin self-administration and relapse. Although SNr GABA neurons are known to form monosynaptic connections with neurons of the ventromedial thalamus (vmThal) and my preliminary data suggest that both regions play a critical role in opioid-driven behaviors, to date, there is no direct evidence of a causal role of the SNr->vmThal pathway in opioid self-administration, relapse and opioid-induced analgesia. To address this critical gap in our knowledge and uncover the novel circuitry underlying pain and opioid addiction, we will combine mouse self-administration with optogenetics and chemogenetic ablations to selectively manipulate the SNr->vmThal pathway. In Specific Aims 1 and 2 we will test the hypothesis that heroin self-administration and heroin-primed drug seeking in are mediated by inhibition of SNr GABA neurons projecting to the vmThal, causing disinhibition of postsynaptic glutamate neurons. In Specific Aim 3, we will determine whether the SNr->vmThal pathway plays a critical role in opioid-induced analgesia, by using optogenetic activation/inactivation or chemogenetic ablation of genetically defined neurons with caspase-3 neurotoxin in hot plate and tail flick assays. Given that woman have higher rates of prescription opioid use than men, we will investigate sex differences in heroin-driven behaviors. These experiments satisfy objectives of NIH Helping to End Addiction Long-term (HEAL) Initiative by linking addiction and pain-related neural substrates and identifying novel circuitry involved in both conditions from which millions of people suffer worldwide. Thus, the proposed research is clinically relevant, as uncovering the neurobiology of opioid addiction and nociception, will set the stage for improving treatment strategies that are desperately needed. Importantly, the proposed experiments are carefully designed with the thought of providing undergraduate students at Colgate University with the unique independent research experience involving cutting-edge techniques to enhance their scientific profile in preparation for careers in the biomedical field.

项目摘要 慢性疼痛是一个重要的临床问题，影响高达20%的一般人群。过- 阿片类镇痛药的处方导致了目前阿片类药物的流行，因为这些药物具有高滥用率 这是由于它们产生的回报效应。因此，改善疼痛和阿片类药物的治疗策略 依赖，有必要揭示这些衰弱条件下的神经机制。阿片 传统上认为奖赏涉及局部GABA对中脑多巴胺神经元的去抑制作用 中间神经元然而，我们最近发现，GABA神经元高表达μ阿片受体， 黑质网状部（SNr）是一个在奖赏和成瘾领域被忽视的大脑区域， 海洛因自我管理和复吸的关键作用。虽然已知SNr GABA神经元形成于 与丘脑腹内侧神经元（vmThal）的单突触连接，我的初步数据表明， 这两个区域在阿片类药物驱动的行为中起着关键作用，到目前为止，还没有直接的证据表明因果关系 SNr-> vmThal途径在阿片类药物自我给药、复发和阿片类药物诱导的镇痛中的作用。解决 这一关键差距，我们的知识和揭示新的电路潜在的疼痛和阿片类药物成瘾，我们将 联合收割机将小鼠自身给药与光遗传学和化学遗传学消融结合， SNr-> vmThal途径。在具体目标1和2中，我们将检验海洛因自我给药和 海洛因引发的药物寻找是通过抑制投射到vmThal的SNr GABA神经元介导的， 突触后谷氨酸神经元的去抑制。在具体目标3中，我们将确定SNr-> vmThal 通过使用光遗传学激活/失活或 在热板和甩尾测定中用半胱天冬酶-3神经毒素化学发生学消融遗传确定的神经元。 鉴于女性处方阿片类药物使用率高于男性，我们将调查 海洛因驱使的行为这些实验满足了NIH帮助长期结束成瘾的目标 （HEAL）通过将成瘾和疼痛相关的神经基质联系起来并确定涉及的新电路来启动 在这两种情况下，全世界数百万人遭受痛苦。因此，拟议的研究是临床 相关的，因为揭示阿片类药物成瘾和伤害感受的神经生物学，将为改善 急需的治疗策略。重要的是，拟议的实验是精心设计的 为高露洁大学的本科生提供独特的独立研究， 涉及尖端技术的经验，以提高他们的科学形象，为未来的职业生涯做准备。 生物医学领域