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

描述(申请人提供)：先前的研究表明，患有经前焦虑症(PMDD)的女性交感神经系统(SNS)和肾上腺素能受体(AR)功能发生变化。我们的工作表明，有性虐待和身体虐待史的PMDD女性，特别是儿童期虐待(CA)的女性，表现出更严重的肾上腺素能失调，因为她们比未受虐待的PMDD女性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)。动物研究清楚地表明，B-AR的激活在产生痛觉过敏中起作用，而NE通路和HPA轴的激活与疼痛抑制有关。因此，在遭受虐待的PMDD妇女中，B-AR功能的改变以及NE和皮质醇输出的减少可能与PMDD中记录的痛敏有关。假设B-AR反应性增加，再加上去甲肾上腺素钝化，将导致更严重的经前症状，并对既往有CA的PMDD女性产生痛觉过敏。60名PMDD妇女和90名非PMDD妇女将在月经周期的黄体期测试静息和应激时SNS(如血浆NE、血压)和HPA轴(皮质醇、ACTH、B-END)的激活情况、B-AR反应性以及对缺血、热痛和冷痛的疼痛敏感度。比较5组疼痛敏感性的差异及其与生理指标的关系：1)有CA史的PMDD妇女(n=30)；2)从未受过虐待的PMDD妇女(n=30)；3)有CA史的非PMDD妇女(n=30)；4)从未受过虐待的非PMDD妇女(n=30)；以及5)无虐待和精神病史的非PMDD妇女(n=30)作为健康对照组。由于我们的初步研究显示，所有有滥用行为的女性皮质醇水平较低，而患有CA的非经前抑郁症女性表现出某种程度的肾上腺素能失调，我们预测PMDD/CA+&gt；non-PMDD/CA+&gt；PMDD/CA-&gt；non-PMDD/CA-对肾上腺素能失调和痛觉过敏的疗效等级顺序。在这项测试之后，使用双盲、安慰剂对照、交叉程序，所有女性将在随后的两个黄体期重新测试SNS测量、疼痛敏感性和烦躁情绪；一次是在小剂量静脉注射期间。普萘洛尔(0.1 mg/kg)，安慰剂期间服用一次。由于心得安是一种B-AR阻滞剂，我们打算使用心得安作为一种药理探针来研究与PMDD痛觉过敏和烦躁情绪有关的SNS和肾上腺素能因素。我们假设心得安将与患有CA的PMDD妇女的SNS、NE和痛觉过敏措施的不同程度的正常化和焦虑症的更大程度的减少相关。这些结果旨在为了解患有CA的PMDD妇女亚组中肾上腺素能激活改变的病理生理学意义提供重要的见解。

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.