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：
10610493
负责人：
CATHERINE M CAHILL
金额：
$ 57.67万
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/10610493
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 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 Photometry Predisposition Prevalence Process Protocols documentation Psychopathology Receptor Activation Receptor Signaling Receptor Up-Regulation 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 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 pharmacologic 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.

抽象的慢性疼痛仅次于躁郁症，是所有医学疾病中自杀的主要原因，抑郁症患病率在30％至80％之间。这种负面影响的重要性反映了在显示共存心理病理学的研究中，可以增加疼痛强度，与疼痛相关的残疾和阿片类药物使用障碍的敏感性。由慢性阿片类药物暴露引起的同种异体适应性，减少但是，奖励自相矛盾的是，它们加强了寻求毒品的行为，这有助于高率慢性疼痛患者的卵毒素滥用和卵毒素使用障碍的发育。选项过程之一慢性药物管理是互动的，包括高层丘脑应力系统，包括增加扩展的杏仁核内皮质激素释放因子和强啡肽的活性（其中包括杏仁核的中央核，CEA）。扩展的杏仁核将压力和奖励系统整合到产生了药物戒断引起的负面情感状态。此外，侧向CEA响应主要是痛苦的刺激被称为“伤心症杏仁核”和副刺激的电路最近，CEA的细胞核参与了有害（痛苦）刺激的厌恶学习。 Dynorphin神经元存在于侧CEA中，其中〜1/3共表达皮质营养素释放因子。该大脑区域已在药物消耗和疼痛中实施。例如，管理 Kappa阿片受体（Kor）拮抗剂Nor-BNI进入CEA，降低了过量的酒精摄入量和化学剂遗传沉默CEA Dynorphin神经元减少了饮酒。还显示了CEA中的KOR信号有助于慢性疼痛引起的厌恶。考虑到CEA参与与持续的疼痛以及这些神经元参与毒品行为，这是我们的主要目的应用是确定杏仁核系统有助于增加毒品行为的程度慢性疼痛。我们将使用针对恢复原状的阿片类药物静脉自我给药的鼠标模型模拟寻求毒品行为的范式。这种范式使我们能够确定kor的程度系统有助于应力引起的恢复。我们的中心假设是慢性疼痛状态领导激活CEA中的KOR系统参与应力诱导的OOID的恢复寻求毒品的行为。提案的目标1将确定CEA Dyn-Kor的必要和充分性负强化的系统。 AIM 2将确定CEA的足够和必要恢复Ooid Plote偏好的dynorphin/kappa Ooid系统。 AIM 3将确定程度应力引起的阿片类药物自我给药的恢复是由CEA中的Kappa阿片类药物驱动的。