Neurochemistry of Opiate Abuse Risk in Chronic Pain

描述(由申请人提供)：实验证据表明，在对滥用药物、应激源的反应以及被认为调节这些反应的神经递质系统的功能上，个体间和性别之间存在重要差异。具体地说，已知多巴胺能(DA)和阿片系统的功能或反应的变化与阿片剂滥用和依赖的发展密切相关。来自我们实验室和其他使用PET和选择性放射示踪剂靶向Mu-阿片和DA-D2受体的其他实验室的最新数据也表明，这些神经递质系统参与疼痛的反应和调节。健康受试者的数据显示，这些神经递质具有相反的作用，DA-D2神经传递增强，Mu-阿片类药物抑制，疼痛报告和疼痛敏感措施。在临床慢性疼痛样本中已经显示出DA-D2受体(增加)和u-阿片受体(减少)的调节，进一步与更高水平的疼痛报告和疼痛敏感性有关。作为对RFA-DA-06-005的响应，本应用程序建立在该初始数据的基础上，以检查慢性疼痛和阿片类药物给药对这些神经递质系统功能的影响。有人建议研究一组诊断为慢性腰痛的患者，无论是否接受阿片类药物治疗，以及年龄和性别匹配的健康对照样本，这些患者的特征都很好。我们将在体内检测慢性疼痛和阿片类药物治疗对mU-阿片和DA-D2受体基线水平的影响。此外，我们建议利用模拟疼痛信号中的天赋的疼痛挑战来确定DA和Mu阿片类药物释放在这三个样本中对疼痛变化的行为反应的参与。然后，这些神经化学测量将与预期评估疼痛、止痛剂需求、典型Mu阿片激动剂芬太尼累积剂量的主观影响以及阿片剂和货币延迟折扣范例中的折扣率的个体差异有关。我们不建议对已知滥用或滥用阿片类药物或依赖阿片类药物的患者进行研究，因为同时滥用或依赖会混淆慢性疼痛和治疗性阿片类药物给药的影响。然而，这些初步研究将在人类中提供有价值的信息，将阿片类药物和DA神经传递的功能与已知可增加随后阿片类药物滥用和滥用风险的因素和结构联系起来(例如，疼痛变异性、对疼痛变化的反应中的痛苦、冲动选择和对急性阿片类药物给药的奖励反应)。

DESCRIPTION (provided by applicant): Experimental evidence points to important interindividual and sex differences in responses to drugs of abuse, stressors, and in the function of neurotransmitter systems thought to mediate those responses. Specifically, variations in the function or responses of dopaminergic (DA) and opioid systems are known to be centrally implicated in the development of opiate abuse and dependence. Recent data from our laboratory and others using PET and selective radiotracers targeting mu-opioid and DA-D2 receptors has also shown that these neurotransmitter systems are involved in the responses and regulation of pain. Data in healthy subjects demonstrates opposing effects of these neurotransmitters, with DA-D2 neurotransmission enhancing, and mu-opioid suppressing, pain reporting and pain sensitivity measures. A modulation of DA-D2 receptors (increases) and mu-opioid receptors (reduced) has been shown in clinical chronic pain samples, further associated with higher levels of pain reporting and pain sensitivity. In response to RFA-DA-06-005, the present application builds on that initial data to examine the effects of chronic pain and opioid administration on the function of these neurotransmitter systems. It is proposed to study a well-charaterized sample of patients diagnosed with chronic lumbar pain either treated or not with opiates and an age- and sex- matched sample of healthy controls. We are to examine the effect of chronic pain and opiate treatment on baseline levels of mu-opioid and DA-D2 receptors in vivo. In addition, we propose to utilize a pain challenge mimicking a flair in the pain signal to determine the involvement of DA and mu-opioid release on behavioral responses to variations in pain in these three samples. These neurochemical measures will then be related to individual differences in prospectively rated pain, analgesic requirements, subjective effects of cumulative doses of the prototypical mu-opioid agonist fentanyl, and rates of discounting in a opiate and monetary delay discounting paradigm. We are not proposing to study patients known to misuse or abuse opiates, or dependent on opiates, as concurrent abuse or dependence would confound the effects of chronic pain and therapeutic opiate administration. However, these initial studies will provide with valuable information in humans, linking the function of opioid and DA neurotransmission with factors and constructs known to confer an elevated risk for the subsequent development of opioid misuse and abuse (e.g., pain variability, distress in responses to variations in pain, impulsive choice and rewarding responses to acute opiate administration).