Neurochemistry of Opiate Abuse Risk in Chronic Pain

描述（由申请人提供）：实验证据表明，在对药物滥用、压力源的反应以及被认为介导这些反应的神经递质系统的功能方面，个体之间和性别之间存在重要差异。具体来说，多巴胺能（DA）和阿片系统的功能或反应的变化被认为是阿片滥用和依赖发展的主要原因。我们的实验室和其他人最近使用PET和选择性放射性示踪剂靶向mu-阿片样物质和DA-D2受体的数据也表明，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性测量。临床慢性疼痛样本显示DA-D2受体（增加）和mu-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相关。为了响应RFA-DA-06-005，本应用程序建立在初始数据的基础上，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。建议对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进行研究。我们将研究慢性疼痛和阿片类药物治疗对体内mu-阿片样物质和DA-D2受体基线水平的影响。此外，我们建议利用模仿疼痛信号的疼痛挑战来确定DA和mu-阿片类药物释放对这三个样本中疼痛变化的行为反应的参与。然后，这些神经化学测量将与个体在预期疼痛评分、镇痛需求、典型的多阿片类激动剂芬太尼累积剂量的主观影响以及阿片类药物和货币延迟折扣范例中的折扣率相关。我们不建议研究已知的误用或滥用阿片类药物或依赖阿片类药物的患者，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的作用。然而，这些初步研究将为人类提供有价值的信息，将阿片类药物和DA神经传递的功能与已知的阿片类药物误用和滥用风险升高的因素和结构联系起来（例如，疼痛变异性，对疼痛变化的反应窘迫，冲动选择和对急性阿片类药物给予的奖励反应）。

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).