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.
Because chronic pelvic pain disorders are widespread neurological public health problems with poorly understood antecedents, this proposal addresses the NINDS goal to reduce suffering from chronic pain by developing a better set of diagnostics for research and clinical evaluation. Our proposed studies translate observations of visceromotor reflexes in animals to humans to establish its value for treating physicians.
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|Zuckerman, Rebecca M; Silton, Rebecca L; Tu, Frank F et al. (2018) Somatic symptoms in women with dysmenorrhea and noncyclic pelvic pain. Arch Womens Ment Health 21:533-541|
|Hellman, Kevin M; Kuhn, Caroline S; Tu, Frank F et al. (2018) Cine MRI during spontaneous cramps in women with menstrual pain. Am J Obstet Gynecol 218:506.e1-506.e8|
|Oladosu, Folabomi A; Tu, Frank F; Hellman, Kevin M (2018) Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment. Am J Obstet Gynecol 218:390-400|