A Model and Mechanism of the Comorbid Interaction between Pain and Anxiety

疼痛与焦虑共病相互作用的模型和机制

• 批准号: 8518095
• 负责人: JIANREN MAO
• 金额: $ 41.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518095
• 关键词: Acute; Affective; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Applications Grants; Area; Attenuated; Basic Science; Behavior; Behavioral; Boxing; Brain; Brain region; Carrageenan; Cell Culture Techniques; Clinical; Comorbidity; Emotional; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Exhibits; Functional Magnetic Resonance Imaging; Goals; Immunohistochemistry; In Situ Hybridization; Injection of therapeutic agent; Knock-out; Knockout Mice; Light; Link; Mandible; Maps; Mediating; Mental Depression; Modeling; Mood Disorders; Neuropeptides; Nociception; Outcome Study; Pain; Pain Disorder; Pain Research; Patients; Peripheral nerve injury; Play; Pre-Clinical Model; Prevalence; Process; Property; Psyche structure; Rattus; Regulation; Risk; Rodent; Role; Spinal Cord; System; Testing; Time; Western Blotting; chronic pain; gamma-Aminobutyric Acid; improved; nerve injury; novel; novel therapeutics; patch clamp; receptor; receptor expression; relating to nervous system; research study; response; subcutaneous; tool

DESCRIPTION (provided by applicant): Pain is often complicated by clinical comorbidities such as anxiety and depression. Most preclinical models, however, do not examine the impact of such comorbidities on pain. For example, while epidemiological studies have consistently shown a comorbid relationship between pain and anxiety, the impact of anxiety on the transition from acute to chronic pain remains unknown largely due to the lack of preclinical models. In an effort to establish a preclinical model of combined pain and anxiety, we recently demonstrated in a set of preliminary experiments that anxiety-like behavior (elevated plus maze, dark-light box test) was induced in rats with persistent, but not transient, nociception from peripheral nerve injury. The presence of anxiety-like behavior prolonged and exacerbated nociceptive behavior. Furthermore, the expression of neuropeptide S (NPS, a novel neuropeptide with an endogenous anxiolytic property) was downregulated, associated with increased basal and stimulation-evoked neural activities (fMRI), in the amygdala of those rats exhibiting nociceptive and anxiety-like behavior. Intracerebroventricular administration of exogenous NPS concurrently improved nociceptive and anxiety-like behavior in the same rats. These preliminary results demonstrate a significant impact of anxiety-like behavior on the transition to chronic pain and suggest that the central NPS system may play a critical role in the comorbid interaction between pain and anxiety. In this grant application, we propose to establish a rat model of combined nociceptive and anxiety-like behavior and use this model to a) evaluate contributions of anxiety-like behavior during the transition from acute to chronic pain and b) determine the role of the central NPS system in the comorbid interaction between pain and anxiety. We will achieve this goal by using behavioral and pharmacological tools, immunohistochemistry, Western blot, real-time PCR, in situ hybridization, cell culture, ELISA, patch-clamp recording, and rodent functional MRI (fMRI). In Specific Aim 1, we will evaluate the impact of nociception-induced vs. genetically pre-disposed anxiety on nociceptive behavior and brain neural activities (rodent fMRI) following transient (subcutaneous carrageenan injection) or persistent (mental nerve injury) nociception in rats. In Specific Aim 2, we will examine a functional role for the central NPS system in nociceptive and anxiety-like behavior using NPS and NPSR (NPS receptor) knockout mice. In Specific Aim 3, we will investigate the neural and cellular mechanism underlying the interaction between pain and anxiety by determining the effect of NPS on a) neural activities in the brain regions implicated in nociceptive processing and emotional/affective response (rodent fMRI) and b) an intra-amygdaloid NPS-GABA link contributory to the regulation of anxiety disorder (patch-clamp recording and cell culture). We anticipate that this project will a) establish a preclinical model useful to examine the impact of anxiety on the transition from acute to chronic pain and b) suggest a strategy for the concurrent treatment of pain and anxiety by regulating the central NPS system.

描述（由申请人提供）：疼痛常常因焦虑和抑郁等临床合并症而变得复杂。然而，大多数临床前模型并未检查此类合并症对疼痛的影响。例如，虽然流行病学研究一致表明疼痛和焦虑之间存在共病关系，但由于缺乏临床前模型，焦虑对急性疼痛向慢性疼痛转变的影响仍然未知。为了建立疼痛和焦虑相结合的临床前模型，我们最近在一系列初步实验中证明，在因周围神经损伤而产生持续性而非短暂性伤害感受的大鼠中，会诱发焦虑样行为（高架十字迷宫、暗灯箱测试）。焦虑样行为的存在会延长并加剧伤害性行为。此外，在表现出伤害性和焦虑样行为的大鼠杏仁核中，神经肽S（NPS，一种具有内源性抗焦虑特性的新型神经肽）的表达下调，与基础神经活动和刺激诱发神经活动（fMRI）的增加相关。脑室内给予外源性 NPS 同时改善了同一大鼠的伤害性和焦虑样行为。这些初步结果表明，类焦虑行为对向慢性疼痛的转变具有显着影响，并表明中枢 NPS 系统可能在疼痛和焦虑之间的共病相互作用中发挥关键作用。在本次拨款申请中，我们建议建立伤害性和焦虑样行为相结合的大鼠模型，并使用该模型来a）评估从急性疼痛向慢性疼痛过渡期间焦虑样行为的贡献，b）确定中枢NPS系统在疼痛和焦虑之间的共病相互作用中的作用。我们将通过使用行为和药理学工具、免疫组织化学、蛋白质印迹、实时 PCR、原位杂交、细胞培养、ELISA、膜片钳记录和啮齿动物功能 MRI (fMRI) 来实现这一目标。在具体目标 1 中，我们将评估大鼠短暂（皮下注射角叉菜胶）或持续（精神神经损伤）伤害感受后，伤害感受诱发的焦虑与遗传预先倾向的焦虑对伤害感受行为和大脑神经活动（啮齿动物功能磁共振成像）的影响。在具体目标 2 中，我们将使用 NPS 和 NPSR（NPS 受体）敲除小鼠来检查中枢 NPS 系统在伤害性和焦虑样行为中的功能作用。在具体目标 3 中，我们将通过确定 NPS 对以下方面的影响来研究疼痛和焦虑之间相互作用的神经和细胞机制：a）涉及伤害感受处理和情绪/情感反应（啮齿动物 fMRI）的大脑区域中的神经活动；b）有助于调节焦虑症的杏仁核内 NPS-GABA 链接（膜片钳记录和细胞培养）。我们预计该项目将 a) 建立一个临床前模型，用于检查焦虑对急性疼痛向慢性疼痛转变的影响；b) 提出一种通过调节中枢 NPS 系统同时治疗疼痛和焦虑的策略。