为什么说第二组患者显示出安慰剂效应？

In an experimental study, patients from a chronic pain clinic are enrolled for a new drug. Experimenters selected patients who did not have opioids in their current medication regimen. In a double-blind study, patients are divided into two arms; placebo (n=30) and the new experimental drug (n=28). End-point measurements for pain included MRI analysis and concurrent CSF sampling at 1, 2, and 6 months. Participants in the first group are given a placebo in addition to their current pain regimen (antidepressants, muscle relaxants, gabapentin). In the second group, patients were given the new experimental drug in addition to their regimen. At month 1 and 2 visits, MRI does not reveal any difference in scans between the groups. At the 6 month mark, MRI scans of the experimental group are largely unchanged, but a significant portion of the placebo group have increased signals in the midbrain and amygdala. Patients in the placebo group also reported increased pain relief in the last 3 months. Experimenters also find distinct differences in the CSF between the experimental and placebo groups. Given these findings on MRI and pain relief in the placebo group, which of the following is most likely expected in the CSF of the second group?

1. Increased enkephalin

2. Decreased IL-1 and IL-6

3. Increased Substance P

4. Increased neurokinin-1

在一项实验研究中，来自慢性疼痛诊所的患者被纳入一种新药。实验人员选择了在他们目前的药物治疗方案中没有阿片类药物的患者。在一项双盲研究中，患者被分成两组；安慰剂（n=30）和新实验药物（n=28）。疼痛终点测量包括1个月、2个月和6个月时的MRI分析和同期脑脊液取样。第一组的参与者除了目前的疼痛疗法（抗抑郁药、肌肉松弛剂、加巴喷丁）外，还服用安慰剂。在第二组患者中，除了他们的方案外，还给予新的实验药物。在第1个月和第2个月的随访中，MRI没有显示两组之间扫描的任何差异。在6个月时，实验组的MRI扫描基本上没有变化，但安慰剂组的很大一部分中脑和杏仁核的信号增加。安慰剂组的患者也报告在过去3个月内疼痛缓解增加。实验人员还发现，实验组和安慰剂组的脑脊液有明显差异。鉴于安慰剂组在MRI和疼痛缓解方面的这些发现，第二组的脑脊液最有可能出现以下哪种情况？

1.脑啡肽增加。

2降低IL-1和IL-6

3P物质增加。

4神经激肽-1增加

Answer: 1 - Increased enkephalin

The patients in the second group are demonstrating the placebo effect in which they are experiencing pain reliefwith no pharmacologic influence. This demonstrates the effect that external expectations and high cortical thinking can influence pain perception. This modulation of pain is largely mediated by the periaqueductal gray (PAG) in the midbrain. Descending projections from the PAG from high cortical structures can attenuate or decrease pain perception via serotonin, norepinephrine, enkephalins, and GABA. This pain relief is also mediated by the release of endogenous opioids. In experimental studies, pain modulation via the PAG has shown increased endogenous opioids such as enkephalins in the spinal cord.The Periaqueductal gray (PAG) has two major downstream pathways in pain control; the locus coeruleus and the rostral ventromedial medulla. The former is mediated via noradrenergic signals and the latter is mediated via serotonergic projections.Pain modulation is bi- directional. Modulation can occur in the spinal cord at the level of the dorsal horn in an ascending manner, or there can be a descending modulation via the periaqueductal gray, amygdala, and higher brain structures. Projections from the periaqueductal grey to the locus coeruleus have been shown to have pro- and anti-nociceptive signals, thus pain can also be augmented.External influences of pain are well known in the placebo effect but have been related to environment and behavior as well. Threatening stimuli are also processed by the periaqueductal gray, with repeated encounters being related to increased modulation ofpain. These amplifications in pain are related to the development of pathologic states such as depression, anxiety, and panic disorder.

答：1-脑啡肽含量增加

第二组患者显示出安慰剂效应，即他们在没有药理学影响的情况下缓解疼痛。这表明外部期望和高皮层思维可以影响疼痛感知。这种疼痛的调节主要由中脑导水管周围灰质（PAG）介导。高皮质结构的PAG下行投射可通过5-羟色胺、去甲肾上腺素、脑啡肽和GABA减弱或减少痛觉。这种疼痛缓解也通过内源性阿片类物质的释放来调节。在实验研究中，通过PAG进行的疼痛调节显示，脊髓内内源性阿片类物质（如脑啡肽）增加。中脑导水管周围灰质（PAG）在疼痛控制中有两条主要的下游通路；蓝斑和头端腹内侧髓质。前者通过去甲肾上腺素能信号介导，后者通过5-羟色胺能投射介导。疼痛调节是双向的。调制可以在脊髓的背角水平以上升的方式发生，也可以通过中脑导水管周围灰质、杏仁核和更高的大脑结构发生下降的调制。从中脑导水管周围灰质到蓝斑的投射被证明具有亲伤害性和抗伤害性信号，因此疼痛也可以增强。疼痛的外部影响在安慰剂效应中是众所周知的，但也与环境和行为有关。恐怖刺激也是通过导水管灰质来处理的，反复的遭遇与增加对疼痛的调制有关。疼痛中的这些扩增与抑郁、焦虑、惊恐障碍等病理状态的发展有关。

为什么说第二组患者显示出安慰剂效应？不是第一组才是placebo吗？