Role of the Amygdala in Opioid Self-administration in Rats with Chronic Pain.

杏仁核在慢性疼痛大鼠阿片类药物自我给药中的作用。

基本信息

批准号：
7460617
负责人：
THOMAS JEFFREY MARTIN
金额：
$ 21.51万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-26 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7460617
关键词：
Acute Acute Pain Affect Amygdaloid structure Analgesics Animals Anterior Area Attenuated Behavior Blood Circulation Brain Brain region Chronic Control Animal Data Development Dose Fire - disasters Glutamates Heroin Hindlimb Hypersensitivity Intake Lead Left Mechanics Medial Medical Methadone Microdialysis Narcotic Antagonists Nerve Neurobiology Neurons Neurotransmitter Receptor Neurotransmitters Nociception Non-Malignant Nucleus Accumbens Opioid Opioid Receptor Pain Pain management Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physical Dependence Physicians Property Psychological reinforcement Rattus Regulation Research Personnel Risk Role Self Administration Self-Administered Series Structure Testing Thalamic structure Time Ventral Tegmental Area Weight-Bearing state addiction beta-funaltrexamine chronic neuropathic pain chronic pain cingulate cortex drug seeking behavior in vivo injured mu opioid receptors nerve injury neurochemistry noradrenergic painful neuropathy prevent programs receptor research study therapy development transmission process

项目摘要

DESCRIPTION (provided by applicant): Opioid therapy for chronic nonmalignant pain is of concern to both patients and physicians regarding addiction and abuse liability. Acute therapy with opioid medications poses limited risks of physical dependence, addiction or problems with diversion of medications. The potential for these adverse consequences greatly increases with long term opioid therapy. Chronic non-malignant pain is a major use of long-term opioid therapy, and often requires relatively large doses of opioids compared to acute pain management. Although much is known about the neurobiology of opioid reinforcement in normal animals, relatively little is known about how chronic pain alters the abuse liability of opioids. Preliminary data indicate that pain from nerve injury selectively attenuates the abuse liability of opioids, and that tolerance to the pain relieving actions of opioids develops rapidly with continuous drug access through self-administration. Furthermore, the abuse liability of opioids is modulated to a much greater extent by manipulating opioid receptors in the amygdala in rats with neuropathic pain compared to normal animals, suggesting that the basic mechanisms responsible for opioid self-administration differ in the presence of chronic pain. Understanding the role of opioid receptors in the amygdala in modulating the abuse liability of opioids selectivley in animals in the presence of chronic pain could lead to therapies that minimize the risk of addiction in pain patients. Studies are proposed to determine how activation of opioid receptors during self-administration produces distinct actions in the amygdala of nerve-injured rats compared to control animals. Neurochemical and pharmacological studies are proposed to determine which neurotransmitters and neurotransmitter receptors are differentially activated during opioid self-administration in normal rats or rats with neuropathic pain. In a second series of studies, the changing role of the amygdala during the development of tolerance to the analgesic effects of opioids will be determined during self-administered dose escalation in normal and nerve-injured rats to determine how the development of tolerance influences the regulation of this brain structure and its' role in the development of addiction. A third series of experiments are proposed that involve manipulating opioid receptors in brain areas known to be involved in classical nociceptive (anterior cingulate cortex, medial thalamus, rostoventral medulla) or reinforcement (nucleus accumbens, ventral tegmental area) pathways to determine which brain regions are primarily responsible for drug-seeking behaviors in the presence or absence of pain in rats. These studies will hopefully define mechanisms that modulate drug-seeking behaviors in the presence of neuropathic pain, and identify potential candidates for therapies that minimize the risk of addiction and physical dependence in pain patients.

描述（由申请人提供）：阿片类药物治疗慢性非恶性疼痛是患者和医生都关心的成瘾和滥用倾向。阿片类药物的急性治疗造成身体依赖、成瘾或药物转移问题的风险有限。长期阿片类药物治疗会大大增加这些不良后果的可能性。慢性非恶性疼痛是长期阿片类药物治疗的主要用途，与急性疼痛治疗相比，通常需要相对较大剂量的阿片类药物。尽管人们对正常动物中阿片类药物强化的神经生物学了解很多，但对于慢性疼痛如何改变阿片类药物的滥用倾向却知之甚少。初步数据表明，神经损伤引起的疼痛选择性地减弱了阿片类药物的滥用倾向，并且通过自我给药持续用药，对阿片类药物缓解疼痛作用的耐受性迅速发展。此外，与正常动物相比，通过操纵患有神经性疼痛的大鼠杏仁核中的阿片受体，阿片类药物的滥用倾向在更大程度上受到调节，这表明阿片类药物自我给药的基本机制在慢性疼痛的情况下有所不同。了解杏仁核中阿片受体在慢性疼痛存在下选择性调节动物阿片类药物滥用倾向中的作用，可能会导致将疼痛患者成瘾风险降至最低的治疗方法。拟进行研究以确定自我给药过程中阿片受体的激活如何在神经损伤大鼠的杏仁核中与对照动物相比产生不同的作用。神经化学和药理学研究旨在确定正常大鼠或患有神经性疼痛的大鼠在阿片类药物自我给药期间哪些神经递质和神经递质受体被差异激活。在第二系列研究中，将在正常和神经损伤大鼠的自我给药剂量递增过程中确定杏仁核在阿片类药物镇痛作用耐受性发展过程中的作用变化，以确定耐受性的发展如何影响调节这种大脑结构及其在成瘾发展中的作用。提出了第三系列实验，涉及操纵已知参与经典伤害性感受（前扣带皮层、内侧丘脑、延髓）或强化（伏核、腹侧被盖区）通路的大脑区域中的阿片受体，以确定哪些大脑区域是主要负责大鼠在存在或不存在疼痛的情况下寻求药物的行为。这些研究有望确定在神经性疼痛存在时调节药物寻求行为的机制，并确定潜在的候选疗法，以最大限度地减少疼痛患者成瘾和身体依赖的风险。