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都关心的成瘾和滥用倾向。使用阿片类药物的急性治疗对身体依赖、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的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，与急性疼痛治疗相比，通常需要相对较大剂量的阿片类药物。虽然人们对正常动物中阿片类药物强化的神经生物学知道得很多，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轻阿片类药物的滥用倾向，随着通过自我给药不断获得药物，对阿片类药物止痛作用的耐受性迅速发展。此外，与正常动物相比，神经性疼痛大鼠杏仁核阿片受体的调节在更大程度上调节了阿片类药物的滥用倾向，这表明在存在慢性疼痛时，负责阿片类药物自我给药的基本机制不同。了解杏仁核阿片受体在调节阿片类药物在慢性疼痛动物中的滥用倾向中的作用，可能会导致将疼痛患者的成瘾风险降至最低的治疗方法。有人建议进行研究，以确定在自我给药过程中，阿片受体的激活如何在神经损伤大鼠的杏仁核中产生与对照动物相比不同的作用。建议进行神经化学和药理学研究，以确定在正常大鼠或神经病理性疼痛大鼠的阿片类药物自我给药过程中，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，将在正常大鼠和神经损伤大鼠自我给药剂量递增的过程中确定杏仁核在阿片类止痛作用耐受性形成过程中的变化作用，以确定耐受性的发展如何影响这种大脑结构的调节及其在成瘾发展中的作用。拟进行的第三系列实验涉及操纵大脑中已知的参与经典伤害性反应(前扣带回、丘脑内侧核、延髓喙腹侧)或强化(伏隔核、腹侧被盖区)通路的阿片受体，以确定在有或没有疼痛的情况下，哪些大脑区域主要负责寻找药物的行为。这些研究有望确定在神经病理性疼痛存在时调节药物寻求行为的机制，并确定将疼痛患者的成瘾风险和身体依赖降至最低的潜在候选疗法。

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.