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内源性大麻素系统介导非阿片类安慰剂镇痛效应在炎性痛中的机制研究
Alternative TitleEndocannabinoid system-mediated neural mechanisms underlying non-opioid placebo analgesia in inflammatory pain
顾丽佳
Subtype博士
Thesis Advisor郭建友
2018-12
Degree Grantor中国科学院心理研究所
Place of Conferral中国科学院心理研究所
Degree Name理学博士
Degree Discipline认知神经科学
Keyword非阿片 安慰剂镇痛 大麻素受体 前边缘皮层 伏隔核
Abstract

安慰剂效应在临床实践中有非常重要的意义,尤其是在疼痛领域,利用安慰剂效应对疼痛进行非药物性的干预,己成为疼痛治疗方案中的一个重要方式。在基础研究方面,研究者逐步揭示了安慰剂镇痛效应的神经生物学机制。目前对其机制的了解主要包括阿片类和非阿片类成分。阿片类成分相对来说,研究得更为广泛和深入,其主要由内源性阿片系统介导。而非阿片成分如何参与安慰剂镇痛,相关机制远未得到揭示。探索安慰剂镇痛的机制有助于揭示心理因素改变疼痛体验的中枢机制,增强临床应用安慰剂效应的理论依据。

本研究中,我们利用经完全弗氏佐剂(Complete Freund's adjuvant, CFA)处理的大鼠,建立炎性痛动物模型。在炎性痛动物中通过镇痛药物阿司匹林进行条件化训练,建立非阿片类安慰剂镇痛的动物模型。在研究一中我们主要采用行为药理学,以及免疫印迹的手段,考察内源性大麻素系统及阿片系统是否参与非阿片类安慰剂效应,并探索介导大麻素系统参与安慰剂效应的关键脑区,观察大麻素受体介导的信号转导通路。研究二利用免疫荧光技术观察非阿片类安慰剂镇痛条件下激活的脑区,并通过行为药理手段确定参与调控非阿片类安慰剂镇痛效应的关键通路。

在炎性痛动物中,我们通过条件化训练成功建立非阿片类安慰剂镇痛效应。并且发现:

1.与我们实验室前期的结果一致,腹腔注射大麻素1型受体(cannabinoid receptor 1, CB1助拮抗剂rimonabant阻断非阿片类安慰剂镇痛效应,而阿片受体拮抗剂naloxone则不能阻断。

2.伏隔核(nucleus accumbens, NAc),而非腹侧海马(ventral hippocampus,vHipp)中微量注射rimonabant显著降低非阿片类安慰剂镇痛作用。

3.内源性大麻素配体N一花生四烯酸乙醇胺(arachidonoyl ethonal amide, AEA)的降解酶,脂肪酞胺水解酶(fatty acid amide hydrolase, FAAH)的抑制剂URB597可增强非阿片安慰剂镇痛效应。

4. NAc中CB1受体,磷酸化PKA,磷酸化CREB蛋白在非阿片类安慰剂镇痛作用下表达上调。

5.非阿片类安慰剂镇痛作用使PL, NAc core, NAc shell脑区的c-Fos蛋白表达增加。

6.通过mPFC内注射药物muscimol失活脑区,发现失活PL,而非IL显著降低非阿片安慰剂镇痛效应。

7.通过两个脑区PL, NAc内交叉注射muscimol,使该通路失活的方式,发现失活PL到NAc的通路阻断非阿片安慰剂镇痛效应。

在以上结果的基础上,我们得到了以下结论:

1.内源性大麻素系统,而非阿片系统特异性地参与了非阿片类安慰剂镇痛作用。

2.首次发现NAc为介导非阿片类安慰剂镇痛的关键脑区,且安慰剂作用依赖于伏隔核(nucleus accumbens, NAc)中CB1受体的激活,该作用可能通过内源性大麻素配体AEA实现的。

3.首次发现NAc中大麻素系统对非阿片类安慰剂镇痛效应的介导作用可能是通过CB 1 R, PKA, CREB信号通路实现。

4.发现PL脑区及PL到NAc的通路在调控非阿片类安慰剂镇痛效应中有重要作用。

Other Abstract

Placebo effect is an important phenomenon in clinical practice, especially used as a non-pharmacological therapy to control pain. As we know more about placebo effect, researchers found that placebo analgesia is induced by different mechanisms.Both opioid and non-opioid elements are involved in placebo analgesia. Past researches reveal that endogenous opioid system patriciates expectation-induced placebo analgesia. However, how non-opioid systems mediate placebo effect is still unknown. Understanding the neural mechanisms underlying placebo analgesia helps us discover how mind interacts with body and changes pain experience, and we could better utilize placebo effect in clinical trials.

The aim of the study is to explore key molecular proteins that mediates non-opioid placebo analgesia and to investigate related brain regions and neural circuits.In study 1,we use behavioral pharmacology and molecular biology techniques to investigate the neuro-biochemical substrates of placebo analgesia. In study 2, we use immunofluorescence and behavioral pharmacology to explore the role of prefrontal cortex一nucleus accumbens in non-opioid placebo analgesia.

The rat model of placebo analgesia is based on Pavlovian conditioning. In this research, to better mimic clinical conditions, we established a new model using Complete Freund's adjuvant-treated rats. First, we injected an antagonist of cannabinoid receptor 1 into nucleus accumbens and ventral hippocampus. Then we explored how endocannabinoid interacts with y一aminobutyric acid in NAc. At last we inactivate mPFC to investigate the neural circuits involves in placebo analgesia. The main results are as follows:

1 .Intraperitoneal injection of antagonist of cannabinoid receptor 1,rimonabant but not naloxone blocked placebo analgesia.

2.Microinjection of rimonabant into nucleus accumbens, but not ventral hippocampus significantly reduces placebo analgesia. Inhibitor of fatty acid amide hydrolase (FAAH) which degrades arachidonoyl ethonal amide enhances placebo analgesia. Furthermore, PA was accompanied by an upregulation of CB 1 receptor, phosphorylated PKA, phosphorylated CREB expression.

3.Immunofluorescence shows an activation of c-Fos expression in PL and NAc.

4. Inactivation of PL, but no IL, diminishes placebo analgesia significantly.

5. Disconnection of PL and NAc blocks placebo analgesia Based on these results, we can conclude that 1) endocannabinoid, but not opioid mediates non-opioid placebo analgesia. 2) nucleus accbumbens is a key region of PA while ventral hippocampus may not participate. PA relies on release of arachidonoyl ethonal amide binding to CB1 in NAc. 3) CB1R mediates placebo analgesia through the activation of p-PKA and p-CREB cascade. 4) prelimbic cortex and nucleus accumbens circuits may specifically participates in non-opioid placebo analgesia.

Pages103
Language中文
Document Type学位论文
Identifierhttp://ir.psych.ac.cn/handle/311026/30405
Collection健康与遗传心理学研究室
Recommended Citation
GB/T 7714
顾丽佳. 内源性大麻素系统介导非阿片类安慰剂镇痛效应在炎性痛中的机制研究[D]. 中国科学院心理研究所. 中国科学院心理研究所,2018.
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