Amygdala kappa opioid system involvement in opioid relapse in pain states

杏仁核卡帕阿片系统参与疼痛状态下阿片类药物复发

基本信息

批准号：
10392180
负责人：
CATHERINE M CAHILL
金额：
$ 57.04万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2022-05-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392180
关键词：
Address Affective Alcohol consumption Amygdaloid structure Anhedonia Animals Anxiety Attenuated Behavior Bipolar Disorder Brain region Cell Nucleus Central Lateral Nucleus Chronic Consumption Corticotropin-Releasing Hormone Data Development Drug Exposure Dynorphins Emotional Exhibits Extinction (Psychology)Fiber Functional disorder Genetic Genetic Models Heavy Drinking Hypothalamic structure Internal Ribosome Entry Site Intravenous Lead Learning Ligands Mediating Medical Medical Records Mental Depression Mental disorders Messenger RNA Modeling Mus Negative Reinforcements Neurons Nociception Opiate Addiction Opioid Opioid Antagonist Opioid agonist Pain Pain Disorder Pain intensity Patients Persistent pain Pharmaceutical Preparations Pharmacology Photometry Predisposition Prevalence Process Protocols documentation Psychopathology Receptor Activation Receptor Signaling Relapse Reporting Research Project Grants Reverse Transcriptase Polymerase Chain Reaction Rewards Risk Factors Rodent Model Self Administration Sensory Spinal Cord Stimulus Stress Suicide System Testing Time addiction animal pain base biological adaptation to stress chronic pain chronic pain patient drug relapse drug seeking behavior drug withdrawal experience genetic approach in vivo kappa opioid receptors motivated behavior mouse model negative affect norbinaltorphimine novel therapeutics opioid epidemic opioid injection opioid misuse opioid overdose opioid use disorder pain-related disability parabrachial nucleus pre-clinical preference prescription opioid receptor expression receptor function receptor upregulation sensory input therapeutic opioid

项目摘要

ABSTRACT Chronic pain is second only to bipolar disorder as the major cause of suicide among all medical illnesses, where prevalence of depression ranges between 30 to 80%. The importance of this negative affect is reflected in studies that show co-existing psychopathology increases pain intensity, pain-related disability and susceptibility for opioid use disorder. Allostatic adaptations caused by chronic opioid drug exposure, diminish reward, however, paradoxically, they reinforce drug-seeking behavior that contributes to the high rates of opioid misuse and development of opioid use disorder in chronic pain patients. One of the opponent processes to chronic drug administration is engagement of extra-hypothalamic stress systems, including increased activity of corticotropin-releasing factor and dynorphin within the extended amygdala (which includes the central nucleus of the amygdala, CeA). The extended amygdala integrates stress and reward systems to produce drug withdrawal-induced negative affective states. Additionally, the lateral CeA responds predominantly to painful stimuli being termed the ‘nociceptive amygdala’ and a circuit from the parabrachial nucleus to the CeA was recently shown to be involved in aversive learning of noxious (painful) stimuli. Dynorphin neurons are present in the lateral CeA, of which ~1/3 co-express corticotrophin releasing factor. This brain region has been implicated in both drug consumption and pain. For example, administration the kappa opioid receptor (KOR) antagonist nor-BNI into the CeA decreased excessive alcohol intake and chemo- genetic silencing CeA dynorphin neurons reduced alcohol drinking. KOR signaling in the CeA was also shown to contribute to chronic pain-induced aversion. Given the involvement of the CeA in aversive learning related to ongoing pain, and the involvement of these neurons in drug-seeking behavior, the primary aim of our application is to determine the extent amygdala KOR system contributes to increased drug-seeking behavior in chronic pain. We will use a mouse model of opioid intravenous self-administration focusing on a reinstatement paradigm that models relapse of drug-seeking behavior. This paradigm allows us to determine the extent KOR systems contribute to stress-induced reinstatement. Our central hypothesis is that chronic pain states lead to activation of KOR systems in the CeA that are involved in stress-induced reinstatement of opioid drug-seeking behavior. Aim 1 of the proposal will determine the necessity and sufficiency of CeA dyn-KOR system in negative reinforcement. Aim 2 will determine the sufficient and necessity of the CeA dynorphin/kappa opioid system in reinstatement of opioid place preference. Aim 3 will determine the extent stress-induced reinstatement of opioid self-administration is driven by the kappa opioid system in the CeA.

抽象的慢性疼痛是所有医学疾病中仅次于躁郁症的第二大自杀原因，抑郁症的患病率在 30% 到 80% 之间，这种负面影响的重要性就得到了体现。研究表明，共存的精神病理学会增加疼痛强度、疼痛相关的残疾和长期阿片类药物暴露引起的阿片类药物使用障碍的易感性减弱。然而，矛盾的是，它们会强化寻求药物的行为，从而导致高比例的药物滥用。阿片类药物滥用和慢性疼痛患者阿片类药物使用障碍的发展是对手过程之一。长期用药的影响在于下丘脑外应激系统的参与，包括增加扩展杏仁核（包括杏仁核）内促肾上腺皮质激素释放因子和强啡肽的活性杏仁核（CeA）的中央核）扩展的杏仁核将压力和奖励系统整合在一起。此外，侧脑区也会产生药物戒断引起的负面情感状态。主要是被称为“伤害性杏仁核”的疼痛刺激和来自臂旁神经的回路最近发现，CeA 核与有害（痛苦）刺激的厌恶性学习有关。强啡肽神经元存在于侧脑区，其中约 1/3 共同表达促肾上腺皮质激素释放因子。该大脑区域与药物消耗和疼痛有关。 kappa阿片受体（KOR）拮抗剂nor-BNI进入CeA过量饮酒和化疗基因沉默 CeA 强啡肽神经元也能减少 CeA 中的 KOR 信号传导。考虑到 CeA 参与与厌恶性学习相关的慢性疼痛引起的厌恶。持续的疼痛，以及这些神经元参与药物寻求行为，这是我们的主要目标该应用的目的是确定杏仁核 KOR 系统在多大程度上有助于增加患者的药物寻求行为我们将使用阿片类药物静脉自我给药的小鼠模型，重点关注恢复。模拟寻求药物行为复发的范式该范式使我们能够确定 KOR 的程度。我们的中心假设是慢性疼痛状态导致恢复。激活 CeA 中的 KOR 系统，该系统参与应激诱导的阿片类药物恢复该提案的目标 1 将确定 CeA dyn-KOR 的必要性和充分性。目标 2 将确定 CeA 的充分性和必要性。强啡肽/卡帕阿片系统在恢复阿片类药物位置偏好中的作用将决定目标 3 的程度。应激诱导的阿片类药物自我给药恢复是由 CeA 中的 kappa 阿片类药物系统驱动的。