Neurophysiological Diagnostics for Menstrual Pain

描述（由申请人提供）：在所有动物研究中用于评价内脏疼痛的试验从未系统地用于人类研究，限制了其可翻译性。研究人员利用内脏运动反射（VMR）和定量感觉测试（QST）的动物模型，在确定内脏疼痛中特定神经通路的参与方面取得了巨大进展。然而，没有在内脏痛患者中研究VMR，并且没有足够的人体数据在临床上使用QST。通过切断神经手术治疗痛经和慢性盆腔痛（CPP）的结果各不相同，因为临床试验无法确定功能障碍的神经或伤害性机制。当靶向内脏或腹下方法的手术方法失败时（30-60%的患者），伤害性感受可能由剩余的神经如阴部神经介导。在动物中，腹斜肌和直肌VMR振幅升高表明盆腔内脏神经敏感。相反，骨盆底敏感性增加则意味着阴部神经受累。人类VMR和QST的类似测量可用于筛选手术候选人。我们建议生成VMR存在于人类中的第一个证据，QST可以使用新的超声电生理方法分离出疼痛表型。初步数据显示，VMR先于疼痛报告，在患有原发性痛经的健康女性中，伴有疼痛的VMR可通过NSAID逆转。因此，我们假设痛经是一种与前列腺素介导的高幅度子宫收缩相关的疾病，这种收缩可能会引起浅表腹部肌肉组织的疼痛。相比之下，患有痛经的女性也患有CPP，在月经来潮期间没有VMR，并且在我们的初步数据中，NSAIDS没有显著减少疼痛报告。我们的初步数据还表明，妇女与CPP有增加阴部敏感性。我们假设CPP与非甾体抗炎药抵抗性痛经（无VMR）和阴部皮区敏感性增加相关。除了我们的假设外，其他可能导致月经痉挛的机制，如子宫收缩、子宫缺血和心理因素，将通过两个目的进行评估：目的#1建立原发性痛经和CPP中VMR和月经痉挛之间的关系。将使用超声和EMG记录VMR，同时监测月经期间自我报告的腹痛或纳鲁生给药前后的自发性内脏痛。目的#2：确定QST表型是否与VMR表型一致，提示腹下神经、盆腔内脏神经或阴部神经受累。将在特定皮区进行感觉测试，以分离这些神经通路在痛经和/或CPP女性中的作用。VMR和QST的表征在改善涉及外显神经和机制靶点的动物模型的可翻译性方面具有重要意义，这是PA 13 -119的目标。

DESCRIPTION (provided by applicant): The tests used to evaluate visceral pain in all animal studies have never been systematically employed in human research, limiting their translatability. Researchers have made enormous progress identifying the involvement of specific neural pathways in visceral pain using animal models utilizing visceral motor reflexes (VMRs) and quantitative sensory testing (QSTs). However, VMRs are not studied in humans with visceral pain and there is insufficient human data to utilize QST clinically. The surgical treatment of dysmenorrhea and chronic pelvic pain (CPP) by transecting nerves has variable outcome because clinical tests do not identify dysfunctional nerves or nociceptive mechanisms. When surgical methods that target the splanchnic or hypogastric methods fail (30-60% of patients), nociception is potentially mediated by remaining nerves such as the pudendal. In animals, elevated abdominal VMR amplitude in the oblique and rectus muscle is indicative of pelvic splanchnic nerve sensitization. In contrast, increased pelvic floor sensitivity implies involvement of the pudendal nerve. Similar measurements of VMR and QST in humans could be used to screen surgical candidates. We propose to generate the first evidence that VMRs exist in humans and that QST can separate out pain phenotypes using novel ultrasound-electrophysiological methods. Preliminary data show that VMRs precede pain report and that VMRs with pain are reversible by NSAIDs in healthy women who suffer from primary dysmenorrhea. Therefore, we hypothesize that dysmenorrhea is a condition associated with prostaglandin mediated high amplitude uterine contractions that may produce pain in the superficial abdominal musculature. In contrast, women with dysmenorrhea who also suffer from CPP did not have VMRs during menstrual cramps and pain report was not significantly reduced by NSAIDS in our pilot data. Our preliminary data also suggest that women with CPP have increased pudendal sensitivity. We hypothesize CPP is associated with NSAID-resistant dysmenorrhea without VMRs and increased sensitivity in the pudendal dermatome. Other mechanisms potentially contributing to menstrual cramps such as uterine contractions, uterine ischemia, and psychological factors in addition to our hypotheses will be evaluated through two aims: Aim #1 To establish the relationship between VMRs and menstrual cramps in primary dysmenorrhea and CPP. VMRs will be recorded with ultrasound and EMG while simultaneously monitoring self-reported abdominal pain during menstruation or spontaneous visceral pain before and after naproxen administration. Aim #2: To determine if QST phenotypes are consistent with VMR phenotypes that suggest hypogastric, pelvic splanchnic, or pudendal nerve involvement. Sensory testing will be performed in specific dermatomes to dissociate the role of these nerve pathways in women with dysmenorrhea and/or CPP. The characterization of VMRs and QST is significant in its ability to improve translatability of animal models that involve explcit neural and mechanistic targets, a goal of PA13-119.