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 慢性疼痛代表了一个重大的临床问题，影响了多达20％的普通人群。超过- 阿片类镇痛药的处方导致当前的阿片类药物流行，因为这些药物遭受了高滥用 由于他们产生的奖励效果而造成的责任。因此，改善疼痛和阿片类药物的治疗策略 依赖性，有必要揭示这些令人衰弱的条件下的神经机制。阿片类药物 传统上，奖励被认为涉及当地GABA对中脑多巴胺神经元的抑制作用 中间神经元。但是，我们最近发现，在 黑质Nigra pars reticulata（SNR），一个大脑区域，在奖励和成瘾领域很大程度上忽略了 在海洛因自我管理和复发中的关键作用。虽然已知SNR GABA神经元形成 与腹膜丘脑神经元（VMTHAL）和我的初步数据的单突触连接 迄今为止，这两个区域在阿片类药物驱动的行为中都起着关键作用 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 我们知识上的这一关键差距，并揭示了疼痛和阿片类药物成瘾的新型电路，我们将 将小鼠的自我给药与光遗传学和化学遗传消融相结合，以选择性操纵 snr-> vmthal途径。在特定目的1和2中，我们将检验海洛因自我管理和 寻求海洛因引用的药物是通过抑制投射到VMTHAL的SNR GABA神经元的介导的 抑制突触后谷氨酸神经元。在特定目标3中，我们将确定SNR-> vmthal是否 途径在阿片类药物诱导的镇痛中起着至关重要的作用，通过使用光遗传激活/失活或 在热板和尾部轻弹测定中用caspase-3神经毒素的遗传学定义神经元的化学解消融。 鉴于妇女的处方阿片类药物使用率比男性高，我们将调查性别差异 海洛因驱动的行为。这些实验满足了NIH的目标，有助于长期结束成瘾 （治愈）主动性通过将成瘾和与疼痛相关的神经底物联系起来并确定涉及的新电路 在这两种情况下，全世界数百万人都会受苦。因此，拟议的研究在临床上是 相关，作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 迫切需要的治疗策略。重要的是，拟议的实验是经过精心设计的 想到为高露洁大学提供本科生提供独特的独立研究 涉及尖端技术以增强其科学概况的经验，以准备职业 生物医学领域。