阿片受体水平和情绪对安慰剂镇痛效应个体差异的影响

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	阿片受体水平和情绪对安慰剂镇痛效应个体差异的影响
其他题名	Individual difference in μ opioid receptor and innate anxiety explains placebo analgesia in rat
	张瑞睿
	2013-05
摘要	安慰剂在常规临床实践中有重要的作用，已有研究表明安慰剂效应是一种情境效应，安慰剂效应的产生是由于社会心理因素诱发病人脑中和躯体中的生化变化，治疗情境导致的预期或情境引起的条件反射引起疼痛症状的缓解。药理学和脑成像研究揭示安慰剂镇痛由内源性阿片肽系统介导的机制及参与镇痛反应的大脑回路的反应机制。但有些个体容易产生安慰剂效应，而另一些则不容易产生安慰剂效应。目前对于安慰剂镇痛效应个体差异的研究还比较缺乏，对安慰剂镇痛个体差异的研究对于临床上实现病人更有效的镇痛具有重要意义。本研究在先前建立的大鼠安慰剂镇痛模型之上研究安慰剂镇痛效应个体差异的影响因素及内在机制，研究目的是揭示阿片受体水平及与之密切相关的焦虑情绪与安慰剂镇痛效应个体差异的相关性，共设计了两个实验。实验一旨在证实rACC是大鼠阿片类安慰剂镇痛的关键脑区，并探究参与阿片类安慰剂镇痛的阿片受体类型。比较在大鼠rACC脑区微注射纳洛酮与腹腔注射纳洛酮对大鼠阿片类镇痛效应的阻断作用；接着在大鼠rACC微注射三种阿片受体拮抗剂，分别是D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 （CTOP）（特异性μ阿片受体拮抗剂）、naltrindole （NTI）（特异性δ阿片受体拮抗剂）和norbinaltorphimine （nor-BNI）（特异性κ阿片受体拮抗剂），以探究参与阿片类安慰剂镇痛的阿片受体类型。实验二是为了探索大鼠的rACC内阿片受体水平、内在焦虑水平与安慰剂镇痛的关系，以揭示安慰剂镇痛效应的个体差异的影响因素。通过高架十字迷宫测试区分大鼠的内在焦虑水平，通过训练建立安慰剂镇痛后，采用Western blot技术检测rACC内阿片受体的蛋白表达量，比较μ阿片受体水平与焦虑情绪的相关性，确定μ阿片受体水平、内在焦虑水平与安慰剂镇痛效应的关系。实验结果采用SPSS、Prism等软件进行分析，结果如下：（1）安慰剂镇痛效应动物模型建立：安慰剂组大鼠第5天上午安慰剂效应测定时的痛阈明显高于第1天上午的基线痛阈，证明顺利建立安慰剂镇痛效应动物模型。（2）腹腔注射纳洛酮三种剂量（0.5，1.5，5mg/kg），只有在剂量为5mg/kg时阻断了安慰剂镇痛效应，而rACC脑区微量注射三种剂量的纳洛酮（1，3，10μg/rat）均能阻断产生安慰剂镇痛效应。（3）rACC脑区微量注射不同剂量的CTOP（0.6，2，6μg/rat），NTI（3，10，30μg/rat），nor-BNI（6，20，60μg/rat），只有中、高剂量CTOP组能阻断产生安慰剂镇痛效应，且表现出剂量依赖效应。（4）大鼠rACC内μ阿片受体水平与安慰剂镇痛效应呈正相关。（5）大鼠内在焦虑水平与rACC内μ阿片受体水平呈负相关，与安慰剂镇痛效应呈负相关。根据以上结果得出如下结论：（1）rACC是大鼠阿片类安慰剂镇痛的重要脑区，其中μ阿片受体介导了这一效应。（2）大鼠rACC内μ阿片受体水平影响安慰剂镇痛效应。（3）大鼠内在焦虑水平可能通过影响μ阿片受体水平而影响安慰剂镇痛效应。
其他摘要	Placebo effect is a biological phenomenon with psychosocial-induced biochemical changes in a patient’s brain and body. The placebo analgesia effect is induced by different mechanisms, including the expectation of pain relief and conditioning. According to pharmacological studies, placebo analgesia is subdivided into opioid and non-opioid components while functional imaging data has also revealed brain regions and brain network involved in placebo analgesia. Previous researches contribute a lot to the understanding of placebo analgesia and its underlying mechanism while the factors influence the variability of placebo analgesia remain unclear. Individual difference in placebo effects has been a hot issue attracting emerging researches recently. This study is aimed to discover the factors influencing placebo analgesia. In 2 experiments, the functional role of μ-opioid receptor and innate anxiety in interanimal variability of placebo analgesia is investigated. In experiment 1, male SD rats were used to explore the site of action and types of opioid receptors involved in placebo response. Rats were trained with 10 mg/kg morphine to establish the placebo analgesia model. This placebo analgesia can be blocked by injection of 5 mg/kg dose naloxone or by microinjection with naloxone (1, 3 or 10 mg/rat) into rostral anterior cingulate cortex (rACC). Then, animals were tested after intra-rACC microinjection of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, a selective μ-opioid receptor antagonist) or naltrindole (NTI, a highly selective d-opioid receptor antagonist) or nor-binaltorphimine (nor-BNI, a highly selective k-opioid receptor antagonist). The results showed that CTOP, but not NTI or nor-BNI, could reduce the pain threshold in placebo analgesia rats. In experiment 2, we want to further explore the association of individual variations in dispositional anxiety with μ-opioid receptor in rACC and placebo analgesia. Naïve male SD rats were submitted to the elevated plus-maze to distinguish the innate anxiety. Then they were trained on a 4-day analgesia conditioning procedure to establish the placebo analgesia. After the placebo analgesia procedure, rats were killed by decapitation, μ-opioid receptor protein expression in rACC was tested using Western blot. The results showed that: (1) Placebo analgesia was tested on day 5 AM and the pain tolerance of placebo group was higher on day 5 AM than the baseline while the natural history group showed no placebo analgesia; (2) μ-opioid receptor protein level in rACC correlated positively with the magnitude of placebo analgesia while correlated non-significantly with the baseline pain threshold; (3) The innate anxiety correlated negatively with the μ-opioid receptor protein level in rACC and magnitude of placebo analgesia. It can be concluded that: (1) rACC is the key brain region involved in placebo analgesia and the opioid placebo analgesia is mediated exclusively through μ-opioid receptor in rat; (2) μ-opioid receptor protein level in rACC influences the magnitude of placebo analgesia; (3) The innate anxiety level may impact μ-opioid receptor protein level, thus influencing the magnitude of placebo analgesia .
学科领域	认知神经科学
关键词	安慰剂镇痛个体差异 μ阿片受体内在焦虑 rACC
学位类型	硕士
语种	中文
学位专业	心理学
学位授予单位	中国科学院研究生院
学位授予地点	北京
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/19765
专题	健康与遗传心理学研究室
作者单位	中国科学院心理研究所
推荐引用方式 GB/T 7714	张瑞睿. 阿片受体水平和情绪对安慰剂镇痛效应个体差异的影响[D]. 北京. 中国科学院研究生院,2013.

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