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

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关注的成瘾和滥用倾向。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。这些不良后果的可能性随着长期阿片类药物治疗而大大增加。慢性非恶性疼痛是长期阿片类药物治疗的主要用途，与急性疼痛管理相比，通常需要相对较大剂量的阿片类药物。虽然对正常动物阿片类药物强化的神经生物学了解很多，但对慢性疼痛如何改变阿片类药物滥用倾向的了解相对较少。初步数据表明，神经损伤引起的疼痛选择性地减弱阿片类药物的滥用倾向，并且对阿片类药物的疼痛缓解作用的耐受性随着通过自我给药的持续药物获取而迅速发展。此外，阿片类药物的滥用倾向在更大程度上通过操纵神经性疼痛大鼠杏仁核中的阿片受体来调节，这表明阿片类药物自我给药的基本机制在慢性疼痛的存在下不同。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中阿片类药物滥用倾向的作用，可能会导致最大限度地降低疼痛患者成瘾风险的治疗。建议进行研究，以确定如何激活阿片受体在自我管理过程中产生不同的行动，在杏仁核神经损伤的大鼠相比，控制动物。神经化学和药理学的研究，建议确定哪些神经递质和神经递质受体的差异激活阿片类药物自我管理过程中，在正常大鼠或大鼠神经病理性疼痛。在第二系列研究中，将在正常和神经损伤大鼠自我给药剂量递增期间确定杏仁核在阿片类镇痛作用耐受性发展期间的变化作用，以确定耐受性的发展如何影响该脑结构的调节及其在成瘾发展中的作用。第三个系列的实验提出，涉及操纵阿片受体在已知参与经典的伤害性（前扣带皮层，内侧丘脑，延髓的嘴腹侧）或强化（核丘脑，腹侧被盖区）的途径，以确定哪些大脑区域是主要负责药物寻求行为的存在或不存在的大鼠疼痛。这些研究将有希望确定在神经性疼痛存在下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。

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.