Chronic opioid self administration in the presence of neuropathic pain

对阿片类药物的广泛研究已经产生了许多关于其镇痛和强化特性的机制的信息。不同的解剖学途径已经阐明了阿片类药物使用拮抗剂和神经毒素诱导的特定神经元群病变的抗痛觉和增强特性。然而，阿片类药物药理学的这两个重要方面在很大程度上是单独研究的。阿片类药物在实验室被动给药后的镇痛作用进行了研究，其中动物不控制剂量或给药间隔。同样，阿片类药物的强化作用是在没有疼痛的情况下在实验室研究的，关于以这种方式确定的强化机制与阿片类药物用于缓解疼痛的临床应用的相关性知之甚少。本项目旨在研究阿片类药物的药理学使用自我用药范式的大鼠神经损伤。这些研究将集中在疼痛存在下阿片耐受性的发展和耐受性机制的探索。给药将通过自我给药来完成，其中允许动物确定达到所需药理学效果所需的药量。这项技术已被证明在药物滥用的研究中是无价的，但正在这个项目中应用于研究疼痛机制，并应提供同样宝贵的信息。实验旨在确定与耐受性发展相关的受体机制，并制定策略，通过24小时自我给药，最大限度地减少耐受性的发展和自我决定的剂量增加。初步数据显示，当给予24小时自我给药时，动物的阿片类药物摄入量迅速增加，并且对阿片类药物的抗异动作用产生耐受性。最初的策略包括使用不同疗效的药物和剂量消退程序，以确定最佳维持剂量，使总剂量随时间的增加最小化。然后，鞘内药物将作为辅助镇痛药给予，作为抑制或延缓阿片类药物耐受性发展和随后剂量增加的另一种策略。平行临床研究提出，以解决这些问题的患者自我管理阿片类药物。这些研究将有望确定阿片类药物自我给药缓解疼痛的耐受性机制和最小化这种影响的策略。

Extensive study of opioids has generated much information regarding the mechanisms of their analgesic and reinforcing properties. Distinct anatomical pathways have been elucidated for the antinociceptive and reinforcing properties of opioids using antagonists and neurotoxin- induced lesions of specific neuronal populations. However, these two important aspects of opioid pharmacology have largely been studied in isolation. The analgesic effects of opioids are studied in the laboratory following passive administration, in which the animal does not control the dose or dosing interval. Similarly, the reinforcing effects of opiates are studied in the laboratory in the absence of pain, and little is known regarding the relevance of reinforcing mechanisms identified in this manner to the clinical use of opioids for pain relief. This project seeks to examine the pharmacology of opioids using a self-medication paradigm in rats with nerve injury. These studies will focus on the development of opioid tolerance in the presence of pain and exploration of the mechanisms of tolerance. Dosing will be accomplished through self-administration, in which the animal is allowed to determine the drug quantity necessary to achieve the desirable pharmacological effect. This technique has proven to be invaluable in the study of drug abuse, but is being applied in this project to the study of pain mechanisms and should provide equally invaluable information. Experiments are designed to determine receptor mechanisms related to the development of tolerance as well as to develop strategies for minimizing the development of tolerance and self-determined dose escalation through experiments using 24 hr self-administration. Preliminary data show that animals rapidly escalate opioid intake when given 24 hr access to self-administration, and that tolerance to the anti-allodynic effects of opioids results. Initial strategies include using drugs of differing efficacies and a dose-fading procedure to determine the optimum maintenance dose that minimized total dose escalation over time. Intrathecal agents will then be given as adjuvant analgesics as another strategy to inhibit or retard the development of tolerance to opioids and subsequent dose escalation. Parallel clinical studies are proposed to address these concerns in patients self-administering opioids. These studies will hopefully identify mechanisms of tolerance to opioids self- administered for pain relief and strategies to minimize such effects.