Mechanisms of pain and placebo analgesia

催产素在社交环境中被释放，而精氨酸加压素主要具有引发焦虑的作用。我们的目标是使用一个公认的自上而下调节疼痛的模型来评估催产素和精氨酸加压素在言语诱导镇痛中的作用。关于催产素和精氨酸加压素对疼痛和社会相互作用的调节功能，我们的大部分知识来自于动物研究，使用中枢给药激动剂和拮抗剂或基因敲除模型。尽管催产素和精氨酸加压素具有社会、抗焦虑和可能的止痛作用，但仍有必要了解催产素和精氨酸加压素在调节人类安慰剂诱导的镇痛中的作用。 我们招募了108名(54名男性，54名女性)健康参与者，并确定了催产素和精氨酸加压素神经肽的作用，它们的功能与社交线索的处理有关(Insel 2010；Meyer-Lindenberg等人)。2011年)在预期诱导止痛方面。我们采用双盲受试者间设计，将健康受试者分配给一次急性给药：1)鼻内注射催产素，2)鼻内注射精氨酸加压素，3)鼻内安慰剂，或4)不治疗。 我们的发现支持这样一个事实，即口头诱导的安慰剂止痛可以通过药物调节。催产素增加了疼痛的耐受性，但不改变安慰剂的止痛效果。相反，精氨酸加压素激动剂与不治疗、安慰剂和催产素相比，安慰剂止痛的幅度增加。与催产素、安慰剂和不治疗相比，精氨酸加压素治疗下观察到的心率变化显示出相反的趋势。精氨酸加压素对皮肤交感反应和唾液皮质醇也有类似的调节作用，与安慰剂和催产素治疗相比，精氨酸加压素的降幅较小。在精氨酸加压素的作用下，焦虑增加。我们的发现表明，VASOPRESSIN能系统通过调节应激反应来影响安慰剂止痛。这些效应表明焦虑、压力和语言诱导的止痛之间存在动态的相互作用(Colloca等人，正在准备中)。 我们收集并开始提取所有参与药理部分和功能磁共振研究的参与者的DNA。对于实验1和实验3中的每个参与者，我们将获得每个候选多态的基因类型。对于每个参与者来说，表型结果包括疼痛和皮质醇的变化。我们使用基因-表型关联统计检验来衡量多态和结果之间的关联。我们还测试了治疗(安慰剂、奥昔洛韦、AVP和不治疗)和性别的线性和二次效应。 最后，我们开始了功能磁共振成像研究。这个过程包括重复暴露在不同的刺激下。视觉刺激包括一组非社交刺激(绿灯、红灯和黄灯)和一组社交线索，其中包括来自Ekman Feest刺激电池的图片。在第一天，受试者通过条件范式(100%偶然性)学习，每种颜色的线索一致地预测不同的热刺激强度。热刺激将在温暖的、非疼痛的温度、中等和中等高温的疼痛温度下进行。表示恐惧、快乐或没有情绪的演员的脸(中性)与热刺激的水平同时显示。彩色脸部配对旨在增强疼痛和无疼痛的预期。在条件化行为阶段之后，热刺激将被设置为与视觉刺激相关的中等水平。根据部分概率强化策略，在MRI中执行的任务期间，同时进行的面部反馈被反转(相对于条件反射)，使得受试者将体验到面部预测。我们已经获得了NIMH科学委员会、白面板IRB、MRI安全委员会的批准，我们已经完成了开始fMRI数据收集的设置。

Oxytocin is released in socially-engaged contexts, while ARGININE VASOPRESSIN has predominantly an anxiogenic effect. Our goal was to evaluate the effects of both OXYTOCIN and ARGININE VASOPRESSIN on verbally-induced analgesia using a well-established model of top-down modulation of pain. Much of our knowledge regarding the regulatory function of OXYTOCIN and ARGININE VASOPRESSIN of pain and social interactions arises from animal studies using central administration of agonists and antagonists or knockout models. Despite its social, anxiolitic/anxiogenic and likely, analgesic effects, there remains a need to understand the role of OXYTOCIN and ARGININE VASOPRESSIN in the modulation of placebo-induced analgesia in humans. We recruited 108 (54 men, 54 women) healthy participants and we determined the role of OXYTOCIN and ARGININE VASOPRESSIN neuropeptides whose function has been associated with the processing of social cues (Insel 2010; Meyer-Lindenberg et al. 2011) in expectancy-induced analgesia. We used a double-blinded between-subject design in which healthy subjects were assigned to a single acute administration of either: 1) intranasal oxytocin, 2) intranasal arginine vasopressin, 3) intranasal placebo, or 4) no-treatment. Our findings support the fact that verbally-induced placebo analgesia can be pharmacologically modulated. OXYTOCIN increased pain tolerance but did not change placebo analgesia. Conversely, ARGININE VASOPRESSIN agonists induced an increase in the magnitude of placebo analgesia as compared to no-treatment, placebo, and oxytocin. Heart rate changes observed under ARGININE VASOPRESSIN treatment show an opposite trend as compared to the effects induced by oxytocin, placebo and no treatment. A similar modulatory effect of ARGININE VASOPRESSIN was observed for the skin sympathetic responses and salivary cortisol that shows less of a decrease under ARGININE VASOPRESSIN as compared to placebo and OXYTOCIN treatments. Anxiety increased under ARGININE VASOPRESSIN. Our findings suggest that the VASOPRESSINergic system influences placebo analgesia by modulating stress responses. These effects indicate a dynamic interplay between anxiety, stress and verbally-induced analgesia (Colloca et al., in preparation). We collected and have started to extract the DNA from all the participants enrolled in the pharmacological part and fMRI study. For each participant in Experiments 1 and 3, we will obtain the genotypes of each candidate polymorphism. For each participant the phenotypic outcomes consist of pain and cortisol changes. We use genotype-phenotype association statistical tests to measure the association between the polymorphisms and outcomes. We also test for linear and quadratic effects of treatment (placebo, OXT, AVP and no-treatment) and gender. Finally, we have begun the fMRI study. The procedure consists of repetitive exposure to different stimuli. Visual stimuli comprise a set of nonsocial (green, red and yellow lights) and a set of social cues consisting of pictures from the Ekman FEEST stimulus battery. On Day 1, subjects learn through a conditioning paradigm (100% contingency) that each colored cue predicts different heat stimulation intensities consistently. Heat stimulation will be delivered at a warm, non-painful temperature, medium and moderately high painful temperature. Faces of actors expressing fear, happiness, or no emotions (neutral) are shown concurrent with the levels of heat stimulation. The color-face pairings are designed to enhance the expectation of pain and no-pain. After the conditioning behavioral phase, the heat stimulation will be set at a medium level in association with the visual stimuli. According to a partial probabilistic reinforcement strategy, during the task performed in the MRI, the concurrent face feedback is reversed (relative to conditioning), such that subjects will experience a face prediction. We have obtained approval by the NIMH Scientific committee, the White Panel IRB, the MRI safety Committee and we have completed the set up starting the fMRI data collection.