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

描述（由申请人提供）：疼痛通常因焦虑和抑郁等临床合并症而复杂化。然而，大多数临床前模型并没有检查这些合并症对疼痛的影响。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，但焦虑对急性疼痛向慢性疼痛转变的影响仍然未知，主要是由于缺乏临床前模型。为了建立一个疼痛和焦虑的临床前模型，我们最近在一组初步实验中证明，焦虑样行为（高架十字迷宫，暗光箱试验）诱导大鼠持续性，但不是短暂的，周围神经损伤的伤害性感受。焦虑样行为的存在延长并加剧了伤害性行为。此外，神经肽S的表达下调，与增加的基础和刺激诱发的神经活动（fMRI），在杏仁核的大鼠表现出伤害性和焦虑样行为的神经肽S（ESTA，一种新的神经肽与内源性抗焦虑的属性）。侧脑室注射外源性多巴胺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，焦虑样行为对慢性疼痛的过渡有显著影响，并表明中枢神经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。在本申请中，我们建议建立一种大鼠伤害性和焦虑样行为的联合模型，并使用该模型a）评估焦虑样行为在急性疼痛向慢性疼痛过渡期间的作用，以及B）确定中枢神经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，Western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性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性（皮下角叉菜胶注射）或持续性（精神神经损伤）伤害感受后，伤害感受诱导的焦虑与遗传易感焦虑对伤害感受行为和脑神经活动（啮齿动物fMRI）的影响。在具体目标2中，我们将使用NPSR和NPSR（NPSR受体）基因敲除小鼠研究中枢神经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，我们将通过确定多巴胺对a）涉及伤害性处理和情绪/情感反应（啮齿动物fMRI）的脑区神经活动和B）有助于调节焦虑症的杏仁核内NPS-GABA连接（膜片钳记录和细胞培养）的影响，研究疼痛和焦虑之间相互作用的神经和细胞机制。我们预期该项目将a）建立一个临床前模型，用于检查焦虑对从急性疼痛向慢性疼痛转变的影响，以及B）提出一种通过调节中枢神经系统同时治疗疼痛和焦虑的策略。 公共卫生相关性：尽管疼痛和疼痛调节的基础科学研究取得了最新进展，但治疗慢性疼痛和相关临床合并症仍然非常困难。目前，大多数临床前模型不能反映疼痛相关合并症对急性疼痛向慢性疼痛转变的影响。这项研究的结果将建立一个临床前模型的疼痛和焦虑，并提出了一个新的治疗选择，同时治疗疼痛和焦虑。

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.