Neurophysiological Diagnostics for Menstrual Pain

描述(申请人提供)：在所有动物研究中用于评估内脏疼痛的测试从未被系统地应用于人类研究，限制了它们的可译性。研究人员利用内脏运动反射(VMRS)和定量感觉测试(QST)建立动物模型，在确定特定神经通路参与内脏疼痛方面取得了巨大进展。然而，VMRS还没有在有内脏疼痛的人类身上进行研究，而且还没有足够的人类数据来临床使用QST。神经切断手术治疗痛经和慢性盆腔疼痛(CPP)有不同的结果，因为临床测试没有发现功能障碍的神经或伤害性机制。当以内脏或下腹部为靶点的手术方法失败时(30%-60%的患者)，伤害感可能是由剩余的神经(如阴部)介导的。在动物中，腹部斜肌和直肌的VMR波幅升高预示着盆腔内脏神经敏感化。相反，盆底敏感性增加意味着阴部神经受累。人体VMR和QST的类似测量可用于筛选手术候选人。我们建议产生第一个证据，证明VMRS在人类中存在，并且QST可以使用新的超声-电生理方法区分疼痛表型。初步数据显示，在患有原发性痛经的健康女性中，VMRS先于疼痛报告，并伴有疼痛的VMRS可被非类固醇抗炎药逆转。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有关的疾病，这种收缩可能会导致腹部浅层肌肉疼痛。相比之下，患有痛经并患有CPP的女性在月经抽筋期间没有出现VMRS，在我们的试点数据中，非甾体抗炎药并没有显著减少疼痛报告。我们的初步数据还表明，患有CPP的女性阴部敏感度增加。我们假设CPP与无VMRS的非甾体类抗炎性痛经和阴部皮肤刀的敏感性增加有关。除了我们的假设之外，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，将通过两个目标进行评估：第一，建立VMRS与原发性痛经和CPP中月经痉挛的关系。VMRS将通过超声波和肌电记录，同时监测月经期间自我报告的腹痛或服用萘普生前后的自发性内脏疼痛。目的#2：确定QST表型与VMR表型是否一致，提示腹下、盆腔内脏或阴部神经受累。感官测试将在特定的皮肤体中进行，以分离这些神经通路在痛经和/或CPP女性中的作用。VMRS和QST的特征在其提高涉及外显神经和机械靶的动物模型的可译性方面具有重要意义，这是PA13-119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.