Neurophysiological Diagnostics for Menstrual Pain

描述（由申请人提供）：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（VMRs）和定量感觉测试（QSTs）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，vmr并没有在患有内脏疼痛的人类中进行研究，并且没有足够的人类数据用于临床应用QST。通过横断神经的手术治疗痛经和慢性盆腔痛（CPP）有不同的结果，因为临床试验不能确定功能障碍的神经或伤害机制。当针对内脏或胃下方法的手术方法失败时（30-60%的患者），伤害感觉可能由阴部等剩余神经介导。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，骨盆底敏感性增加暗示阴部神经受累。人体VMR和QST的类似测量可用于筛选手术候选人。我们提出了第一个证据，证明vmr存在于人类中，QST可以使用新的超声电生理方法分离疼痛表型。初步数据显示，原发痛经的健康女性出现vmr先于疼痛报告，且伴有疼痛的vmr可通过非甾体抗炎药逆转。因此，我们假设痛经是一种与前列腺素介导的高振幅子宫收缩相关的疾病，这种子宫收缩可能产生腹部浅表肌肉组织疼痛。相比之下，在我们的试点数据中，患有CPP的痛经妇女在痛经期间没有VMRs，并且非甾体抗炎药的疼痛报告没有显着减少。我们的初步数据还表明，患有CPP的女性阴部敏感性增加。我们假设CPP与非甾体抗炎药抵抗性痛经无vmr和阴部皮肤敏感性增加有关。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，将通过以下两个目的进行评估：目的1：建立原发性痛经和CPP患者vmr与月经痉挛之间的关系。用超声和肌电图记录vmr，同时监测服用萘普生前后自我报告的月经期间腹痛或自发性内脏疼痛。目的2：确定QST表型是否与提示下胃、盆腔内脏或阴部神经受累的VMR表型一致。将在特定的皮节中进行感觉测试，以分离这些神经通路在痛经和/或CPP妇女中的作用。VMRs和QST的表征在提高涉及明确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.