NEUROENDOCRINE ALTERATIONS IN FIBROMYALGIA AND IBS

这项提案的长期目标是了解慢性功能性疼痛综合征的病因，如纤维肌痛（FM）和肠易激综合征（IBS）。 FM和IBS中的症状群表明未能适当激活疼痛调节机制，未能激活神经内分泌应激机制，以及自主反应的改变。 我们的一般假设是，FM和IBS患者中存在一种神经生物学模型，其主要组成部分包括以下CNS对应激源的反应改变：抗伤害性反应不足，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。 通过在两种功能性疼痛综合征（FM，IBS和IBS + FM）中应用类似的方法，我们将阐明这些功能性疾病是否共享改变的CNS回路，或者是否具有位点特异性，并可能解释躯体或内脏领域症状表达的差异。 第一个目的是比较内脏和躯体疼痛阈值之前和之后的伤害性条件刺激在三个女性患者人群（IBS，FM和IBS + FM）与女性对照组，这将使我们能够确定是否改变知觉反应是由于过敏传入通路，或未能激活抗伤害性系统。 为了进一步表征特定抗伤害性通路在条件刺激下的激活变化，我们将评估阿片系统（芬太尼，纳洛酮）和去甲肾上腺素能系统（促肾上腺皮质激素释放激素（CRH），地塞米松）的药理学操作对疼痛阈值的影响。 最后，我们将比较已知在4个研究人群中在条件刺激前后的内脏和躯体刺激期间，H215 O PET脑成像在抗伤害感受中发挥核心作用的区域中的脑激活。 在第二个目标中，我们将在4个研究人群中测试HPA轴的反应性，这在FM患者中已被证明是改变的，并解决解释这些HPA轴改变的潜在机制。 为了表征这些变化，我们将在24小时内连续测量血浆皮质醇和ACTH，以评估昼夜脉动节律和ACTH和皮质醇同步性的基线变化。 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条件反射范式中内脏和躯体刺激的自主反应。 为了确定研究组之间中枢自主神经网络对内脏或躯体刺激的反应是否不同，将使用协变量分析将PET研究中内脏和躯体刺激期间的局部脑激活与自主神经反应相关。 实验方法的结合应提高我们对功能性疼痛综合征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.