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

描述(申请人提供)：疼痛通常是由临床并发症，如焦虑和抑郁。然而，大多数临床前模型并没有研究这种并存对疼痛的影响。例如，虽然流行病学研究一直表明疼痛和焦虑之间存在共病关系，但焦虑对从急性疼痛向慢性疼痛过渡的影响仍不清楚，这主要是因为缺乏临床前模型。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，周围神经损伤导致持续但不是短暂的伤害性感觉的大鼠可以诱导焦虑样行为(抬高加迷宫，暗光盒测试)。焦虑样行为的存在延长并加剧了伤害性行为。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(一种新的具有内源性抗焦虑特性的神经肽)的表达下调，并伴随着基础和刺激诱发神经活动(FMRI)的增加。脑室注射外源性NPS可同时改善相同大鼠的伤害性行为和焦虑样行为。这些初步结果表明，焦虑样行为对向慢性疼痛的转变有显著影响，并提示中枢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。在这项拨款申请中，我们建议建立一个大鼠伤害性行为和焦虑性行为相结合的模型，并使用该模型来a)评估焦虑样行为在从急性疼痛到慢性疼痛过渡过程中的作用，以及b)确定中枢NPS系统在疼痛和焦虑之间的共生相互作用中的作用。我们将通过使用行为和药理学工具、免疫组织化学、Western印迹、实时聚合酶链式反应、原位杂交、细胞培养、ELISA、膜片钳记录和啮齿动物功能磁共振(FMRI)来实现这一目标。在具体目标1中，我们将评估伤害性焦虑和遗传性焦虑对大鼠短暂(皮下注射角叉菜胶)或持续性(精神神经损伤)伤害性行为和脑神经活动(啮齿类fMRI)的影响。在特定的目标2中，我们将使用NPS和NPSR(NPS受体)基因敲除小鼠来检验中枢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a)涉及伤害性处理和情绪/情感反应的大脑区域的神经活动(啮齿动物fMRI)和b)杏仁核内参与焦虑症调节的NPS-GABA联系(膜片钳记录和细胞培养)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。我们预计，该项目将a)建立一个临床前模型，用于研究焦虑对从急性疼痛到慢性疼痛的转变的影响，以及b)通过调节中枢NPS系统，为疼痛和焦虑的同时治疗提供一种策略。 公共卫生相关性：尽管最近在疼痛和疼痛调制的基础科学研究方面取得了进展，但治疗慢性疼痛及其相关的临床合并症仍然非常困难。目前，大多数临床前模型没有反映疼痛相关并发症在从急性疼痛向慢性疼痛过渡过程中的影响。这项研究的结果将建立一个疼痛和焦虑相结合的临床前模型，并为同时治疗疼痛和焦虑提供一种新的治疗选择。

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. PUBLIC HEALTH RELEVANCE: Despite recent progresses in basic science research of pain and pain modulation, it remains very difficult to treat chronic pain and the related clinical comorbidities. Currently, most preclinical models do not reflect the impact of pain-related comorbidities on the transition from acute to chronic pain. The outcome of this study will establish a preclinical model of combined pain and anxiety and suggest a new therapeutic option for the concurrent treatment of both pain and anxiety.