Opioid Self-Administration in Chronic Pain

描述（由申请人提供）：阿片类药物仍然是治疗许多慢性疼痛病症的最有效药物治疗剂。然而，滥用阿片类药物的可能性可能会影响使用它们的决定，特别是在治疗非癌症疼痛方面。阿片耐受、依赖、成瘾和一些慢性疼痛病症都具有共同的神经适应机制。因此，在个体中区分这些反应是具有挑战性的。中枢给药方法（如鞘内给药）能够将慢性疼痛机制（大部分由脊柱介导）与驱动动机性行为的机制（脊柱上介导）进行一定程度的分离。拟议的研究计划将在慢性疼痛的实验鼠模型中使用这些技术，以将用于缓解慢性痛觉过敏的芬太尼自我给药（口服）与超过缓解痛觉过敏所需的阿片类药物自我给药（抗痛觉过敏）分开。将允许具有后爪的诱导的慢性神经性或癌症诱发的痛觉过敏的实验受试者在操作控制下每天口服自我施用阿片样物质，持续四周;将在每次操作会话后测定所得的抗痛觉过敏。将在痛觉过敏诱导后的不同日期鞘内给予补救性抗痛觉过敏剂，以评估脊髓抗痛觉过敏对阿片类自我给药的影响。确定脊髓给药的补救镇痛剂对阿片类药物自我给药的影响，将能够评估阿片类药物用于抗痛觉过敏的量，而不依赖于用于脊髓上介导的奖励的自我给药。将进一步评价在存在足够脊髓镇痛剂的情况下继续自我给予阿片类药物的受试者，以确定使其倾向于阿片类药物自我给药超过抗痛觉过敏所需剂量的脊髓上机制。相反，将评价减少阿片类药物自我给药以响应脊髓镇痛剂（用于缓解机械性痛觉过敏）的实验受试者的保护其免受过量阿片类药物自我给药的因素。澄清阿片类药物在治疗慢性疼痛时被滥用的条件可能会更好地为治疗过程的决策提供信息。 公共卫生相关性：人们认为，慢性疼痛患者服用阿片类镇痛药更多是为了缓解疼痛，而不是寻求奖励;然而，对滥用责任的恐惧往往限制了它们的使用，导致慢性疼痛治疗不足。阿片类药物自我管理和慢性疼痛强度之间的关系很少在实验动物中进行研究。在经历慢性疼痛的小鼠中模拟阿片类药物自我给药将提供对这一概念的深入了解，并最终改善患者获得阿片类药物治疗其疼痛的途径。

DESCRIPTION (provided by applicant): Opioids remain the most effective pharmacotherapeutics for the treatment of many chronic pain conditions. However, the potential for misuse of opioids can impact the decision to use them, particularly in the treatment of non-cancer pain. Opioid tolerance, dependence, addiction and some chronic pain conditions all share common mechanisms of neuronal adaptation. Consequently, distinguishing between these responses in an individual is challenging. Central drug delivery methods (e.g. intrathecal) enable some separation of chronic pain mechanisms (in large part spinally mediated) from those driving motivated behavior (supraspinally mediated). The proposed research program will use these techniques in experimental murine models of chronic pain to separate fentanyl self-administered (orally) for relief of chronic hyperalgesia from opioid self- administered in excess of that required for relief of hyperalgesia (anti-hyperalgesia). Experimental subjects with induced chronic neuropathic or cancer-evoked hyperalgesia of the hindpaw will be allowed to self-administer opioid orally under operant control daily for four weeks; the resulting anti-hyperalgesia will be determined after each operant session. Rescue anti-hyperalgesic agents will be administered intrathecally on various days after induction of hyperalgesia to assess the impact of spinal anti-hyperalgesia on opioid self-administration. Determining the effect of spinally administered rescue analgesic on opioid self-administration will enable an assessment of the amount of opioid administered for anti-hyperalgesia independent of that self-administered for supraspinally mediated reward. Those subjects continuing to self-administer opioid in the presence of adequate spinal analgesic will be further evaluated to determine supraspinal mechanisms that pre-dispose them to opioid self-administration in excess of that required for anti-hyperalgesia. Conversely, experimental subjects that reduce opioid self-administration in response to spinal analgesic (for alleviation of mechanical hyperalgesia) will be evaluated for factors that protect them from excess opioid self-administration. Clarification of the conditions under which opioids are misused when given for treatment of chronic pain may better inform the decision-to-treat process. PUBLIC HEALTH RELEVANCE: Chronic pain sufferers are thought to take opiate analgesics more for pain relief than in search of reward; however, fear of abuse liability often limits their use, resulting in undertreatment of chronic pain. The relationship between opiate self-administration and chronic pain intensity is rarely studied in experimental animals. Modeling opioid self- administration in mice experiencing chronic pain will provide insight into this concept and ultimately improve patient access to opioid therapy for their pain.