An Animal Model of Therapeutic Self-Medication for Neuropathic Pain

描述（由申请人提供）：本申请“神经性疼痛的治疗性自我药物治疗的动物模型”解决了广泛的挑战领域（15）转化科学和特定的挑战主题，15-DA-112：临床前慢性疼痛研究中的新模型和措施。我们的长期目标是发现抑制人类缺乏药物滥用倾向的病理性疼痛的机制。本申请的目的是验证用于评估非精神活性镇痛剂的治疗性自我用药的动物模型。我们的新方法将镇痛自我管理行为的评估与抗伤害感受和依赖的行为评估相结合。我们的中心假设是，动物将自我麻醉与非精神活性大麻素止痛剂，以减轻神经性疼痛状态。这些研究具有创新性，因为它们利用了通常用于研究滥用药物的积极强化作用的技术方法，并将这些方法应用于新的背景。在此，药物自我给药用于研究假定镇痛药的负强化特性（即减弱神经性疼痛状态的能力）和在存在和不存在神经损伤的情况下的依赖性。研究人员有能力开展这项工作，因为我们已经开发了一种新的临床前模型，该模型表明动物将自我施用非精神活性大麻素镇痛剂以减轻神经性疼痛状态。因此，我们相信我们的自我药疗模式具有广泛的转化价值。我们将完成根据两个特定目的提出的实验：1）为了检验大鼠将自我施用非精神活性大麻素镇痛剂以减轻神经性疼痛状态的假设，2）为了检验相对于阿片镇痛剂吗啡，非精神活性大麻素镇痛剂将产生最小依赖性（拮抗剂促戒断和条件性位置厌恶）的假设。该项目的完成预计将验证一种新的临床前模型，用于评估镇痛疗效和药物滥用倾向。开发有效的药物治疗疼痛，最大限度地减少滥用的可能性，预计将降低医疗保健成本，减轻患者的痛苦。 公共卫生相关性：疼痛是美国人进入医疗保健系统的首要原因。据估计，疼痛治疗不足每年造成的社会经济成本为1 000亿美元。拟议的工作将开发和验证一种用于止痛药治疗性自我给药的大鼠模型。开发安全有效的药物，没有滥用的可能性是必要的，以降低医疗保健成本，提高患者的生活质量。

DESCRIPTION (provided by applicant): The present application "An Animal Model of Therapeutic Self-Medication for Neuropathic Pain" addresses the broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DA-112: New Models and Measures in Preclinical Chronic Pain Research. Our long-term goal is to uncover mechanisms for suppressing pathological pain that lack drug abuse liability in humans. The objective of this application is to validate an animal model for assessing therapeutic self-medication of non-psychoactive analgesics. Our novel approach combines assessments of analgesic self-administration behavior with behavioral assessments of antinociception and dependence. Our central hypothesis is that animals will self-medicate with a nonpsychoactive cannabinoid analgesic to attenuate a neuropathic pain state. These studies are innovative because they exploit technological approaches commonly employed to study positive reinforcing effects of abused drugs and apply these methods to a novel context. Here, drug self-administration is used to study negative reinforcing properties of putative analgesics (i.e. ability to attenuate a neuropathic pain state) and dependence liability in the presence and absence of nerve injury. The investigators are well-positioned to conduct the proposed work because we have developed a new preclinical model which demonstrates that animals will self-administer a nonpsychoactive cannabinoid analgesic to attenuate a neuropathic pain state. We, consequently, believe that our self-medication model has broad translational value. We will complete experiments proposed under two Specific Aims: 1) To test the hypothesis that rats will self-administer a nonpsychoactive cannabinoid analgesic to attenuate a neuropathic pain state, 2) To test the hypothesis that a nonpsychoactive cannabinoid analgesic will produce minimal dependence (antagonist-precipitated withdrawal and conditioned place aversion), relative to the opiate analgesic morphine. Completion of this project is expected to validate a novel preclinical model for assessing both analgesic efficacy and drug abuse liability. The development of effective pharmacotherapies for pain with minimal abuse liability is expected to drive down health care costs and alleviate suffering in patients. PUBLIC HEALTH RELEVANCE: Pain is the number one reason Americans access the health care system. Socioeconomic costs of inadequate treatment for pain are estimated at $100 billion annually. The proposed work will develop and validate a rat model for therapeutic self-medication of analgesics. Development of safe and effective drugs that lack abuse potential is necessary to drive down health care costs and improve quality of life in patients.