Circulating sex steroids and bladder pain sensitivity in dysmenorrhea.

Although elevated estradiol levels facilitate chronic pelvic pain in animal models, it remains to be determined whether sex steroid levels are altered in a cross-section of women with chronic pelvic pain (CPP) and those at-risk for developing CPP. We sought to determine if sex steroid levels are increased in women with menstrual pain and whether those changes were more extreme in two groups of women with worsened pelvic pain profiles: a) dysmenorrhea plus evidence of bladder pain sensitivity and b) bladder pain syndrome. Serum samples were collected during the mid-luteal phase to measure estradiol, progesterone, testosterone, and sex hormone-binding globulin. We also compared quantitative sensory testing profiles to evaluate how sex steroid differences influence proposed pain sensitivity mechanisms. Women with combined dysmenorrhea and bladder sensitivity had higher estradiol concentrations than controls (487 [IQR 390 - 641] vs 404 [336 - 467] pmol/L, p = 0.042). Bladder pain syndrome participants had greater sex hormone-binding globulin than controls (83 [71 - 108] vs 55 [42 - 76 nmol/L; p = 0.027). Levels of pain sensitivity and mood were different across the groups, but the only significant relationship to sex steroids was that sex hormone-binding globulin was correlated to somatic symptoms (r = 0.26, p = 0.03). These findings show women potentially at-risk for CPP and women with diagnosed CPP exhibit altered circulating levels of sex steroids. Because these hormonal differences appear to be independent of mood or pain sensitivity, the role of sex steroids in the emergence of CPP may be via sensitization of visceral afferents.

Dysmenorrhea subtypes exhibit differential quantitative sensory assessment profiles.

Women who develop bladder pain syndrome (BPS), irritable bowel syndrome, or dyspareunia frequently have an antecedent history of dysmenorrhea. Despite the high prevalence of menstrual pain, its role in chronic pelvic pain emergence remains understudied. We systematically characterized bladder, body, and vaginal mechanical sensitivity with quantitative sensory testing in women with dysmenorrhea (DYS, n = 147), healthy controls (HCs) (n = 37), and women with BPS (n = 25). Previously, we have shown that a noninvasive, bladder-filling task identified a subset of women with both dysmenorrhea and silent bladder pain hypersensitivity, and we repeated this to subtype dysmenorrhea sufferers in this study (DYSB; n = 49). DYS, DYSB, and BPS participants had lower vaginal mechanical thresholds and reported more pain to a cold stimulus during a conditioned pain modulation task and greater pelvic examination after-pain than HCs (P's < 0.05). DYSB participants also had reduced body mechanical thresholds and less conditioned pain modulation compared to HCs and DYS participants (P's < 0.05). Comparing quantitative sensory testing results among the DYS and HC groups only, provoked bladder pain was the only significant predictor of self-reported menstrual pain (r = 0.26), bladder pain (r = 0.57), dyspareunia (r = 0.39), and bowel pain (r = 0.45). Our findings of widespread sensory sensitivity in women with dysmenorrhea and provoked bladder pain, much like that observed in chronic pain, suggest a need to study the trajectory of altered mechanisms of pain processing in preclinical silent visceral pain phenotypes to understand which features convey inexorable vs modifiable risk.

Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment.

Although nonsteroidal antiinflammatory drugs can alleviate menstrual pain, about 18% of women with dysmenorrhea are unresponsive, leaving them and their physicians to pursue less well-studied strategies. The goal of this review is to provide a background for treating menstrual pain when first-line options fail. Research on menstrual pain and failure of similar drugs in the antiplatelet category suggested potential mechanisms underlying nonsteroidal antiinflammatory drug resistance. Based on these mechanisms, alternative options may be helpful for refractory cases. This review also identifies key pathways in need of further study to optimize menstrual pain treatment.

Novel intrathecal and subcutaneous catheter delivery systems in the mouse.

BACKGROUND: Catheter systems that permit targeted delivery of genes, molecules, ligands, and other agents represent an investigative tool critical to the development of clinically relevant animal models that facilitate the study of neurological health and disease. The development of new sustained catheter delivery systems to spinal and peripheral sites will reduce the need for repeated injections, while ensuring constant levels of drug in plasma and tissues. NEW METHOD: Here, we introduce two novel catheter delivery systems in the mouse: the O'Buckley intrathecal catheter system for sustained delivery to the spinal region and a subcutaneous bifurcated catheter system for sustained drug delivery to both hindpaws. RESULTS: The O'Buckley intrathecal catheter system consistently distributed Evans Blue throughout the spinal cord, with the greatest concentration at the thoracic region, and with an 85% surgery success rate. The subcutaneous catheter system consistently distributed Evans Blue to the hindlimbs, with a 100% surgery success rate. COMPARISON TO EXISTING METHOD: The O'Buckley intrathecal catheter system accomplishes sustained drug delivery to the spinal region, with a 2-fold increase in surgery success rate, as compared to the traditional method. Our subcutaneous bifurcated catheter system accomplishes sustained drug delivery to both hindpaws, eliminating the need for repeated intraplantar injections. CONCLUSIONS: We have developed catheter systems that improve upon traditional methods in order to achieve sustained localized drug delivery to spinal tissues and to hindpaw tissues surrounding peripheral sciatic nerve terminals. These methods have a broad reach, and can be used to enhance behavioral, physiologic and mechanistic studies in mice.

Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation.

Nuclear factor-kappa B (NF-κB) is a ubiquitously expressed protein complex regulating the transcription of genes involved in inflammation and pain. Increased NF-κB activity in immune and nervous system cells is linked to several chronic pain conditions in humans as well as inflammation and nerve injury-evoked pain in animals. A recent in vitro study further demonstrates that increased NF-κB activity in astrocytes decreases transcription of catechol-o-methyltransferase (COMT), an enzyme that inactivates catecholamines that cause pain. The purpose of the present study was to examine the relationship between systemic and astrocytic NF-κB activity, pain, and COMT expression in an animal model of inflammation. Results demonstrated that administration of the inflammatory stimulant complete Freund's adjuvant (CFA) led to increased pain and decreased COMT protein expression in an NF-κB-dependent manner. Specifically, we found that rats and mice receiving intraplantar CFA exhibited increased behavioral responses to mechanical and thermal heat stimuli. CFA-evoked pain was blocked in rats receiving a pre-emptive systemic dose of the NF-κB inhibitor MG132 and exacerbated in IKKca mice with constitutive NF-κB activity in astrocytes. Furthermore, we observed NF-κB-linked reductions in COMT expression in midbrain at 6h and 1d following CFA in rats and at 1h and 1d in forebrain and midbrain following CFA in IKKca mice. Collectively, these results demonstrate that systemic and astrocytic NF-κB activity drive inflammatory pain and regulate the expression of COMT in forebrain and midbrain structures.