Chronic pelvic pain (CPP) disorders cause significant distress and often lack effective treatments. Although dysmenorrhea is closely associated with 80% of cases of CPP, little is known about why only some women with menstrual pain go on to develop conditions like interstitial cystitis/bladder pain syndrome, irritable bowel syndrome, or endometriosis. Intriguingly, 20% of dysmenorrhea sufferers (without chronic pain) display a key feature of many CPP states, bladder hypersensitivity on noninvasive bladder filling, and appear on pilot studies at higher risk of CPP in one year. In this team’s prior studies, women with the dysmenorrhea with bladder pain phenotype (DYSB) also exhibit greater somatic symptom burden, experimental pain hypersensitivity, and psychological dysregulation—features found in many chronic pain patients. As little is known about the acute to CPP transition, this renewal application seeks to track pelvic pain symptomatology prospectively in DYSB women and to expand those initial mechanistic studies. Aim 1 is a two-year longitudinal study of 1050 young women oversampled for dysmenorrhea to find 150 DYSB cases and establish their risk trajectory for CPP symptoms vs. those with only dysmenorrhea (DYS only = 750) and healthy controls (HC = 150). Along with a virtual bladder filling screening test, other patient health factors potentially predicting development of CPP will be captured, including overall pelvic experiences and general sensory sensitivity. Aim 2 will investigate 100 DYSB and 100 controls (DYS only and HC) on two dimensions of CPP mechanistically—bladder hypersensitivity and multimodal hypersensitivity (a composite of experimentally evoked responses to nonvisceral quantitative sensory tests [QST]). Electroencephalography-based studies will further investigate which neurological mechanisms (i.e. ascending neural hyperexcitability, descending inhibition, and neural oscillations) underlie these two components and predict one-year worsening of CPP symptoms. Aim 3 studies whether another key mechanism of pain sensitization, Toll-like Receptor-4 inflammatory reactivity, influences CPP progression, using an integrated whole-blood collection and leukocyte culture system. This renewal application significantly extends this discovery of an at-risk phenotype by providing a method for expanding screening and characterizing reversible mechanisms. This essential followup study utilizes innovative combinations of QST with EEG measurements of brain activity to identify the mechanisms responsible for CPP-related-sensory abnormalities, alongside measures of systemic inflammatory reactivity that are strongly implicated in sensory hypersensitivity. Notably, if these are confirmed, candidate early interventions already exist to modulate these mechanisms, including mindfulness meditation and consistent anti-inflammatory use for dysmenorrhea. Successful completion of these studies would accelerate efforts to prevent the transition from acute ...