化学遗传沉默蓝斑-基底外侧杏仁核通路可消除大鼠疼痛诱导的焦虑和增强的厌恶学习。

Chemogenetic Silencing of the Locus Coeruleus-Basolateral Amygdala Pathway Abolishes Pain-Induced Anxiety and Enhanced Aversive Learning in Rats.

机构信息

Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain; Biomedical Research Networking Center for Mental Health Network (CIBERSAM), Institute of Health Carlos III, Madrid, Spain; Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, Puerta del Mar University Hospital, University of Cádiz, Cádiz, Spain; Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain.

Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, Cádiz, Spain; Biomedical Research Networking Center for Mental Health Network (CIBERSAM), Institute of Health Carlos III, Madrid, Spain; Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, Cádiz, Spain.

出版信息

Biol Psychiatry. 2019 Jun 15;85(12):1021-1035. doi: 10.1016/j.biopsych.2019.02.018. Epub 2019 Mar 5.

DOI:10.1016/j.biopsych.2019.02.018

PMID:30987747

Abstract

BACKGROUND

Pain affects both sensory and emotional aversive responses, often provoking anxiety-related diseases when chronic. However, the neural mechanisms underlying the interactions between anxiety and chronic pain remain unclear.

METHODS

We characterized the sensory, emotional, and cognitive consequences of neuropathic pain (chronic constriction injury) in a rat model. Moreover, we determined the role of the locus coeruleus (LC) neurons that project to the basolateral amygdala (BLA) using a DREADD (designer receptor exclusively activated by designer drugs).

RESULTS

Chronic constriction injury led to sensorial hypersensitivity in both the short term and long term. Otherwise, long-term pain led to an anxiety-like profile (in the elevated zero maze and open field tests), as well as increased responses to learn aversive situations (in the passive avoidance and fear conditioning tests) and an impairment of nonemotional cognitive tasks (in the novel object recognition and object pattern of separation tests). Chemogenetic blockade of the LC-BLA pathway and intra-BLA or systemic antagonism of beta-adrenergic receptors abolished both long-term pain-induced anxiety and enhanced fear learning. By contrast, chemogenetic activation of this pathway induced anxiety-like behaviors and enhanced the aversive learning and memory index in sham animals, although it had little effect on short- and long-term chronic constriction injury animals. Interestingly, modulation of LC-BLA activity did not modify sensorial perception or episodic memory.

CONCLUSIONS

Our results indicate that dimensions associated with pain are processed by independent pathways and that there is an overactivation of the LC-BLA pathway when anxiety and chronic pain are comorbid, which involves the activity of beta-adrenergic receptors.

摘要

背景

疼痛会引起感觉和情感上的厌恶反应，慢性疼痛通常会引发焦虑相关疾病。然而，焦虑和慢性疼痛之间相互作用的神经机制尚不清楚。

方法

我们在大鼠模型中描述了神经病理性疼痛（慢性缩窄性损伤）的感觉、情感和认知后果。此外，我们使用 DREADD（专门被设计药物激活的受体的设计者）确定了投射到基底外侧杏仁核（BLA）的蓝斑核（LC）神经元的作用。

结果

慢性缩窄性损伤导致短期和长期的感觉过敏。此外，长期疼痛导致出现类似焦虑的症状（在高架十字迷宫和旷场试验中），以及增加对学习厌恶情况的反应（在被动回避和恐惧条件反射试验中），并损害非情感认知任务（在新颖物体识别和物体模式分离试验中）。LC-BLA 通路的化学遗传阻断以及 BLA 内或全身β-肾上腺素能受体拮抗剂均消除了长期疼痛引起的焦虑和增强的恐惧学习。相比之下，该通路的化学遗传激活在假手术动物中引起类似焦虑的行为，并增强了厌恶学习和记忆指数，尽管它对短期和长期慢性缩窄性损伤动物几乎没有影响。有趣的是，LC-BLA 活性的调节不会改变感觉知觉或情景记忆。