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疾病最有效的药物治疗药物。然而，滥用阿片类药物的可能性会影响使用它们的决定，特别是在治疗非癌症疼痛时。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，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）使慢性疼痛机制（主要是脊柱介导的）与驱动动机行为（脊柱上介导的）在一定程度上分离开来。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，将用于缓解慢性痛觉过敏的芬太尼自我给药（口服）与用于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。患有慢性神经性或癌症诱发的后肢痛觉过敏的实验对象将被允许在操作控制下每天口服阿片类药物，持续四周；每次手术后确定抗痛觉过敏的效果。我们将在痛觉诱导后的不同天内鞘内给予救援抗痛觉药物，以评估脊髓抗痛觉药物对阿片类药物自我给药的影响。确定脊髓给药对阿片类药物自我给药的影响将使评估抗痛觉过敏的阿片类药物给药量独立于棘上介导奖励的自我给药量。那些在有足够的脊髓镇痛药的情况下继续自我给药阿片类药物的受试者将被进一步评估，以确定使他们倾向于自我给药阿片类药物超过抗痛觉过敏所需的椎上机制。相反，减少阿片类药物自我给药以应对脊髓镇痛（减轻机械性痛觉过敏）的实验对象将被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。

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.