Childhood Trauma in the Adrenergic and HPA-Axis Regulation and Symptoms of PMDD

描述（由申请人提供）：先前的研究表明，女性经前烦躁不安（PMDD）有交感神经系统（SNS）和肾上腺素能受体（AR）功能的改变。我们的研究表明，有性虐待和身体虐待史的经前抑郁症女性，特别是童年虐待（CA）的女性，与未受虐待的经前抑郁症女性相比，她们表现出更高的心率和血压水平，更高的B-AR反应性和更低的血浆去甲肾上腺素（NE），因此肾上腺素能失调更严重。动物研究清楚地表明B-AR激活在产生痛觉过敏中起作用，而NE通路和hpa -轴激活参与疼痛抑制。因此，经前抑郁女性B-AR功能的改变、NE和皮质醇输出的减少可能与经前抑郁中记录的痛觉过敏有关。假设B-AR反应性增加加上NE变钝将导致经前焦虑症患者经前症状加重以及痛觉过敏和实验性疼痛。60名经前焦虑症患者和90名非经前焦虑症患者将在月经周期的黄体期测试静息和应激时的SNS（如血浆NE、血压）和hpa轴（皮质醇、ACTH、b端）激活、B-AR反应性以及对缺血、热痛和冷痛的疼痛敏感性。将比较五组疼痛敏感性的差异及其与生理指标的关系：1)有CA病史的经前抑郁妇女（n=30）；2)从未虐待经前不悦症妇女（n=30）；3)既往CA的非经前不悦女性（n=30）；4)从未虐待过非经前不悦症妇女（n=30）；5)无虐待和无精神病史的非经前抑郁症妇女（n=30）作为健康对照组。由于我们的初步研究表明，所有受虐妇女的皮质醇水平都较低，而患有CA的非经前不悦症妇女表现出一定程度的肾上腺素能失调，我们预测了PMDD/CA+>非PMDD/CA+>PMDD/CA->非PMDD/CA-对肾上腺素能失调和痛觉过敏的影响程度。在此测试之后，使用双盲、安慰剂对照、交叉程序，所有女性将在随后的2个黄体期重新测试社交网络测量、疼痛敏感性和烦躁情绪；低剂量普萘洛尔静脉注射一次（0.1 mg/kg），安慰剂注射一次。由于心得安是一种B-AR阻滞剂，我们打算用心得安作为药理学探针来研究SNS和肾上腺素能因子对经前抑郁中痛觉过敏和烦躁情绪的影响。我们假设，心得安与经前不悦症合并CA的女性的SNS、NE和痛觉过敏措施的不同程度的更大正常化以及更大程度的烦躁减少有关。这些结果旨在为经前不悦症合并CA的女性亚组肾上腺素能激活改变的病理生理意义提供重要见解。

DESCRIPTION (provided by applicant): Prior research indicates that women with premenstrual dysphoric disorder (PMDD) have alterations in sympathetic nervous system (SNS) and adrenergic receptor (AR) function. Our work suggests that PMDD women with histories of sexual and physical abuse, especially childhood abuse (CA) show even greater adrenergic dysregulation, since they exhibit greater heart rate and blood pressure levels, greater B-AR responsivity and lower plasma norepinephrine (NE) relative to non-abused PMDD women. Animal studies clearly indicate a role for B-AR activation in producing hyperalgesia, while NE pathways and HPA-axis activation are involved in pain inhibition. Thus, alterations in B-AR function and diminished NE and cortisol output in PMDD women with abuse may have implications for the hyperalgesia that has been documented in PMDD. It is hypothesized that increased B-AR responsivity coupled with blunted NE will contribute to worse premenstrual symptoms and to hyperalgesia to experimental pain in PMDD women with prior CA. Sixty PMDD and 90 non-PMDD women will be tested in the luteal phase of the menstrual cycle for SNS (e.g., plasma NE, blood pressure) and HPA-axis (cortisol, ACTH, B-end) activation at rest and during stress, B-AR responsivity, and pain sensitivity to ischemic, thermal heat, and cold pain. Five groups will be compared for differences in pain sensitivity and relationship to physiological measures: 1) PMDD women with prior CA (n=30); 2) never abused PMDD women (n=30); 3) non-PMDD women with prior CA (n=30); 4) never abused non-PMDD women (n=30); and 5) non-PMDD women with no abuse and no psychiatric histories (n=30) as a healthy control group. Since our prelim studies show that all women with abuse have lower cortisol and non- PMDD women with CA show some degree of adrenergic dysregulation, we predict a rank order of effects PMDD/CA+>non-PMDD/CA+>PMDD/CA->non-PMDD/CA- for adrenergic dysregulation and hyperalgesia. Following this testing, using double-blind, placebo-controlled, cross-over procedures, all women will be retested in 2 subsequent luteal phases for SNS measures, pain sensitivity, and dysphoric mood; once during a low dose, i.v. propranolol session (0.1 mg/kg) and once during placebo. Since propranolol is a B-AR blocker, we intend to use propranolol as a pharmacological probe to investigate SNS and adrenergic factors that contribute to hyperalgesia and dysphoric mood in PMDD. We hypothesize that propranolol will be associated with differentially greater normalization of SNS, NE and hyperalgesia measures, and greater reductions in dysphoria in PMDD women with CA. These results are intended to provide important insights into the pathophysiological significance of altered adrenergic activation in the subgroup of PMDD women with CA.