Imaging Drugs with and without Clinical Analgesic Efficacy
Imaging Drugs with and without Clinical Analgesic Efficacy
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DOI：
10.1038/npp.2011.156
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发表时间：
2011-12-01
影响因子：
7.6
通讯作者：
Borsook, David
中科院分区：
文献类型：
--
作者：
Upadhyay, Jaymin;Anderson, Julie;Borsook, David
对疼痛的行为反应由感觉和情感成分驱动，每种成分都由CNS介导。在评价潜在镇痛剂时，使用主观疼痛评级作为读数;然而，仅疼痛评级无法表征疼痛处理期间的CNS疼痛回路或该回路如何被调制。具有潜在镇痛作用的更客观的读数可以允许改善对疼痛的药理学功效的理解和检测。药理学/功能磁共振成像（phMRI/fMRI）方法可用于客观评价药物对CNS的作用。在这种情况下，我们的目的是评估两种已开发的镇痛药：一种是有效的疼痛（丁丙诺啡（BUP））和一个失败的镇痛药在临床试验阿瑞匹坦（APREP）。使用phMRI，我们观察到仅由BUP诱导的激活存在于具有μ阿片受体的区域中，而APREP诱导的激活存在于表达NK 1受体的区域中。然而，仅在BUP给药后观察到疼痛处理途径中功能连接的显著药理学调节。通过实施诱发疼痛的功能磁共振成像范例，这些药物也可以区分通过比较各自的功能磁共振成像信号在中枢神经系统电路介导的感觉和情感成分的疼痛。我们报告的相关性功能连接和诱发疼痛功能磁共振测量疼痛评级以及峰值药物浓度。这项调查表明如何CNS作用的药物可以比较，以及如何phMRI/fMRI方法可以与传统的措施，以更好地评估候选镇痛药在小受试者队列。Neuropsychopharmacology（2011）36，2659-2673; doi：10.1038/npp.2011.156; 2011年8月17日在线发表
The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with mu-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK1 receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts. Neuropsychopharmacology (2011) 36, 2659-2673; doi: 10.1038/npp.2011.156; published online 17 August 2011