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

• 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
• 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

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.

摘要 在所有内科疾病中，慢性疼痛是仅次于双相情感障碍的自杀主要原因， 抑郁症的患病率在30%到80%之间。这种负面影响的重要性也得到了反映。 研究表明，同时存在的精神病理学会增加疼痛强度、疼痛相关残疾和 阿片类药物使用障碍的易感性。慢性阿片类药物暴露引起的变态适应，减弱 然而，自相矛盾的是，它们强化了寻求毒品的行为，这导致了高吸毒率 阿片类药物滥用与慢性疼痛患者阿片类药物使用障碍的发展。其中一个对手进程 慢性用药是下丘脑外应激系统的参与，包括增加 延伸杏仁核内促肾上腺皮质激素释放因子和强啡肽的活性(包括 杏仁中央核(CEA)。延伸的杏仁核整合了压力和奖励系统，以 产生药物戒断引起的负面情绪状态。此外，横向CEA响应 主要是痛性刺激，被称为‘伤害性杏仁核’和来自臂旁核的环路 最近发现，CEA核参与了对伤害性(痛苦)刺激的厌恶学习。 强啡肽神经元存在于外侧CEA，其中~1/3共表达促肾上腺皮质激素释放因子。 这一大脑区域与药物消耗和疼痛有关。例如，管理 Kappa阿片受体(KOR)拮抗剂Nor-BNI进入CEA可减少过量酒精摄入和化疗。 基因沉默的CEA强啡肽神经元减少了饮酒。还显示了CEA中的KOR信号 导致慢性疼痛引起的厌恶情绪。鉴于CEA参与了与以下相关的厌恶学习 持续的疼痛，以及这些神经元参与药物寻找行为，我们的主要目标是 应用于确定杏仁核KOR系统在多大程度上有助于增加患者的药物寻求行为 慢性疼痛。我们将使用阿片类药物静脉注射自我给药的小鼠模型，重点是恢复 对毒品寻觅行为复发进行建模的范例。这一范例允许我们确定KOR的程度 系统有助于压力诱导的恢复。我们的中心假设是慢性疼痛状态导致 激活CEA中参与应激诱导的阿片类药物恢复的KOR系统 寻找毒品的行为。提案的目标1将确定CEA dyn-kor的必要性和充分性 系统处于负强化状态。目标2将确定CEA的充分和必要性 强啡肽/kappa阿片系统在恢复阿片位置偏爱中的作用。目标3将决定 应激诱导的阿片自我给药的恢复是由CEA中的kappa阿片系统驱动的。