Opioid Self-Administration in Chronic Pain

描述(申请人提供)：阿片类药物仍然是治疗许多慢性疼痛情况的最有效的药物疗法。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。阿片类药物耐受、依赖、成瘾和一些慢性疼痛状况都有共同的神经元适应机制。因此，区分个体的这些反应是具有挑战性的。中枢给药方法(如鞘内给药)使慢性疼痛机制(很大程度上由脊髓调节)与驱动动机行为的机制(棘上调节)得到一定程度的分离。拟议的研究计划将在慢性疼痛的实验小鼠模型中使用这些技术，将自行(口服)缓解慢性疼痛的芬太尼与超过缓解疼痛(抗痛觉过敏)所需的阿片类药物分开。患有诱发的慢性神经性或癌症诱发的后爪痛敏的实验受试者将被允许在手术控制下每天自我口服阿片类药物，为期四周；所产生的抗痛觉过敏将在每次手术后确定。在痛觉过敏诱导后的不同时间鞘内给予抢救性抗痛敏药物，以评估脊髓抗痛敏药物对阿片类药物自身给药的影响。确定脊髓给药的解救止痛剂对阿片类药物自身给药的影响，将有助于评估用于抗痛敏的阿片类药物的量，而不是自我给药以获得棘上介导的奖赏。那些在有足够的脊椎止痛剂存在的情况下继续自我给予阿片类药物的受试者将被进一步评估，以确定使他们预先给予超过抗痛敏所需的阿片类药物自我给予的脊髓上机制。相反，对脊髓止痛剂(用于缓解机械痛敏)而减少阿片类药物自我给药的实验受试者，将评估保护他们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情况可能会更好地为决定治疗过程提供信息。 公共卫生相关性：慢性疼痛患者服用阿片类镇痛剂更多的是为了缓解疼痛，而不是为了寻求回报；然而，对滥用责任的恐惧往往限制了他们的使用，导致对慢性疼痛的治疗不足。在实验动物中，阿片类药物自身给药与慢性疼痛强度之间的关系很少被研究。在经历慢性疼痛的小鼠中建立阿片类药物自我给药模型将提供对这一概念的见解，并最终改善患者获得阿片类药物治疗疼痛的机会。

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.