NEUROENDOCRINE ALTERATIONS IN FIBROMYALGIA AND IBS

这项建议的长期目标是发展对慢性功能性疼痛综合征的病因学的理解，如纤维肌痛(FM)和肠易激综合征(IBS)。FM和IBS的一系列症状表明，未能适当激活疼痛调制机制，未能激活神经内分泌应激机制，以及自主神经反应改变。我们的一般假设是，FM和IBS患者存在神经生物学模型，其主要组成部分包括以下中枢系统对应激源反应的变化：抗伤害反应不足，下丘脑-垂体-肾上腺(HPA)轴反应迟钝，自主神经平衡和反应性改变。通过对两种功能性疼痛综合征(FM、IBS和IBS+FM)应用类似的方法，我们将阐明这些功能性疾病是否共享改变的中枢神经系统回路，或者是特定于部位的，并可能解释躯体或内脏区域症状表达的差异。第一个目的是比较三个女性患者群体(IBS、FM和IBS+FM)在伤害性条件反射刺激前后的内脏和躯体痛阈值，这将使我们能够确定知觉反应的改变是由于超敏传入通路，还是由于未能激活抗伤害感受系统。为了进一步研究特定的抗伤害感受通路对条件性刺激反应的激活变化，我们将评估阿片系统(芬太尼、纳洛酮)和去甲肾上腺素系统(促肾上腺皮质激素释放激素(CRH)、地塞米松)的药理操作对痛阈值的影响。最后，我们将在4个研究人群中比较在条件性刺激前后内脏和躯体刺激期间，在内脏和躯体刺激期间，已知在抗伤害感受中发挥核心作用的区域的大脑激活情况。在第二个目标中，我们将在4个研究人群中测试已被证明在FM患者中改变的HPA轴的响应性，并解决解释这些HPA轴改变的潜在机制。为了确定这些变化的特征，我们将获得24小时内血浆皮质醇和ACTH的连续测量，以评估ACTH和皮质醇的昼夜节律和同步性的基线变化。我们还将通过比较内脏或躯体条件刺激前后的ACTH和皮质醇水平来评估HPA轴对急性应激的反应。最后，在我们的第三个目标中，我们将比较内脏和躯体刺激在内脏和躯体条件反射范例中的自主神经反应。为了确定中枢自主神经网络对内脏或躯体刺激的反应是否在研究组之间有所不同，在PET研究中，使用协变量分析将局部脑激活与内脏和躯体刺激期间的自主神经反应相关联。实验方法的结合将提高我们对功能性疼痛综合征潜在的中枢神经系统机制的理解。

The long-range goal of this proposal is to develop an understanding of the etiology of chronic functional pain syndromes, such as fibromyalgia (FM) and irritable bowel syndrome (IBS). The constellation of symptoms in the FM and IBS suggest a failure to appropriately activate pain modulatory mechanisms, a failure to activate neuroendocrine stress mechanisms, and an alteration in the autonomic response. Our general hypothesis is that a neurobiological model exists in patients with FM and IBS, which includes as its primary components alterations in the following CNS responses to stressors: inadequate antinociceptive response, blunted hypothalamic-pituitary-adrenal (HPA) axis response and altered autonomic balance and responsiveness. By applying similar methodologies across two functional pain syndromes (FM, IBS, and IBS plus FM), we will elucidate if altered CNS circuits are shared by these functional disorders or are site-specific and may explain the differences in symptom expression in the somatic or visceral domains. The first aim is compare the visceral and somatic pain thresholds before and after a noxious conditioning stimulus in three female patient populations (IBS, FM and IBS plus FM) with female controls, which would allow us to determine if altered perceptual responses are due to hypersensitive afferent pathways, or to a failure to activate antinociceptive systems. To further characterize alterations in the activation of specific antinociceptive pathways in response to conditioning stimuli, we will assess the effect of pharmacological manipulations of the opioid system (fentanyl, naloxone), and the noradrenergic system (corticotropin-releasing hormone (CRH), dexamethasone) on pain thresholds. Finally, we will compare brain activation in regions known to play central roles in antinociception in the 4 study populations with H215O PET brain imaging during visceral and somatic stimuli before and after the conditioning stimulus. In the second aim, we will test the responsiveness of the HPA axis, which has been shown to be altered in patients with FM, in the 4 study populations and address the potential mechanisms to explain these HPA axis alterations. To characterize these alterations, we will obtain serial measurements of plasma cortisol and ACTH over a 24-hour period to assess baseline alterations in the diurnal pulsatile rhythm and synchrony of ACTH and cortisol. We will also assess HPA axis responsiveness to acute stress by comparing ACTH and cortisol levels before and after a visceral or somatic conditioning stimulus. Finally, in our third aim, we will compare autonomic responses to visceral and somatic stimuli during visceral and somatic conditioning paradigms. In order to determine if the response of central autonomic networks to visceral or somatic stimulation differ between the study groups, regional brain activation will be correlated to autonomic responses during the visceral and somatic stimuli in the PET studies using covariate analysis. The combination of experimental approaches should improve our understanding of the CNS mechanisms underlying functional pain syndromes.