Sensory mapping of pelvic dermatomes in women with interstitial cystitis/bladder pain syndrome.

AIM: To describe a sensory map of pelvic dermatomes in women with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We hypothesized that if IC/BPS involves changes in central processing, then women with IC/BPS will exhibit sensory abnormalities in neurologic pelvic dermatomes. METHODS: Women with IC/BPS and healthy controls underwent neurologic examination that included evaluation of sharp pain sensitivity and vibration in dermatomes T12, L1, L2, S1-5. Peripheral nervous system sensitivity to pressure, vibration, and pinprick were scored using numeric rating scales (NRS). Bilateral comparisons were made with Wilcoxon signed-rank test and comparisons between groups were made by the Mann-Whitney U-test. RESULTS: Total of 74 women with IC/BPS and 36 healthy counterparts were included. IC/BPS and control groups had similar age (43.0 ± 14.1 and 38.6 ± 15.3 years, P = 0.14) and BMI (28.9 ± 8.0 kg/m2 and 26.9 ± 8.4 kg/m2 , P = 0.24), respectively. Women with IC/BPS reported hyperalgesia (elevated bilateral NRS pain intensity) in all pelvic dermatomes compared to healthy controls. S4-S5 region had the highest pain intensity in all participants. All IC/BPS participants exhibited vibration sensation hypoesthesia, at least unilaterally, in all of the pelvic dermatomes except L1 compared to healthy controls. CONCLUSION: This detailed map of neurologic pelvic dermatomes in women with IC/BPS found hyperalgesia in all pelvic dermatomes, and some evidence of vibration sensation hypoesthesia, compared to healthy controls. These findings support the hypothesis that IC/BPS may involve changes in central signal processing biased towards nociception.

Corticotropin-releasing factor family peptide signaling in feline bladder urothelial cells.

Corticotropin-releasing factor (CRF) plays a central role in the orchestration of behavioral and neuroendocrine responses to stress. The family of CRF-related peptides (CRF and paralogs: urocortin (Ucn)-I, -II, and -III) and associated receptors (CRFR1 and CRFR2) are also expressed in peripheral tissues such as the skin and gastrointestinal tract. Local signaling may exert multiple effects of stress-induced exacerbation of many complex syndromes, including psoriasis and visceral hypersensitivity. Interstitial cystitis/painful bladder syndrome (IC/PBS), a chronic visceral pain syndrome characterized by urinary frequency, urgency, and pelvic pain, is reported to be exacerbated by stress. Functional changes in the epithelial lining of the bladder, a vital blood-urine barrier called the urothelium, may play a role in IC/PBS. This study investigated the expression and functional activity of CRF-related peptides in the urothelium of normal cats and cats with feline interstitial cystitis (FIC), a chronic idiopathic cystitis exhibiting similarities to humans diagnosed with IC/PBS. Western blots analysis showed urothelial (UT) expression of CRFR1 and CRFR2. Enzyme immunoassay revealed release of endogenous ligands (CRF and Ucn) by UT cells in culture. Evidence of functional activation of CRFR1 and CRFR2 by receptor-selective agonists (CRF and UCN3 respectively) was shown by i) the measurement of ATP release using the luciferin-luciferase assay and ii) the use of membrane-impermeant fluorescent dyes (FM dyes) for fluorescence microscopy to assess membrane exocytotic responses in real time. Our findings show evidence of CRF-related peptide signaling in the urothelium. Differences in functional responses between FIC and normal UT indicate that this system is altered in IC/PBS.

Effects of stressors on the behavior and physiology of domestic cats.

Feline interstitial cystitis (FIC) is a chronic pain syndrome of domestic cats. Cats with FIC have chronic, recurrent lower urinary tract signs (LUTS) and other comorbid disorders that are exacerbated by stressors. The aim of this study was to evaluate behavioral and physiological responses of healthy cats and cats diagnosed with FIC after exposure to a five day stressor. Ten healthy cats and 18 cats with FIC were housed at The Ohio State University Veterinary Medical Center (OSUVMC) vivarium. All cats were housed in enriched cages for at least one year prior to the experiment. Cats had daily play time and socialization outside of the cage, food treats and auditory enrichment. The daily husbandry schedule was maintained at a consistent time of day and cats were cared for by two familiar caretakers. During the test days, cats were exposed to multiple unpredictable stressors which included exposure to multiple unfamiliar caretakers, an inconsistent husbandry schedule, and discontinuation of play time, socialization, food treats, and auditory enrichment. Sickness behaviors (SB), including vomiting, diarrhea, anorexia or decreased food and water intake, fever, lethargy, somnolence, enhanced pain-like behaviors, decreased general activity, body care activities (grooming), and social interactions, were recorded daily. Blood samples were collected in the morning, before and after the stress period, for measurement of serum cortisol concentration, leukocytes, lymphocytes, neutrophils, neutrophil: lymphocyte (N:L) ratio and mRNA for the cytokines interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Overall, the short term stressors led to a significant increase in SB in both healthy cats and cats with FIC, whereas lymphopenia and N:L changes occurred only in FIC cats. Daily monitoring of cats for SB may be a noninvasive and reliable way to assess stress responses and overall welfare of cats housed in cages.

Pharmacodynamic effects of ivabradine, a negative chronotropic agent, in healthy cats.

OBJECTIVE: To determine the pharmacodynamic effects of oral ivabradine in cats. ANIMALS: Eight healthy, adult domestic short hair cats. METHODS: Each cat underwent four study periods of 24 h, receiving either one dose of placebo or ivabradine (0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) in a single-blind randomized crossover study. Clinical tolerance was assessed hourly for the first 8 h, at 12 h, and at the end of the 24-h study period. Heart rate and blood pressure were monitored continuously for 18-24 h via radiotelemetry after each treatment. Response to stress (acoustic startle) was studied before (t = 0) and after treatment (t = 4 h). Statistical comparisons were made using a linear mixed models and 1-way and 2-way repeated measures ANOVA. RESULTS: Heart rate (min(-1)) decreased significantly (P < 0.05) in a dose-dependent manner with peak negative chronotropic effects observed 3 h after ivabradine (mean ± SD; placebo, 144 ± 20; ivabradine 0.1 mg/kg, 133 ± 22; ivabradine 0.3 mg/kg, 112 ± 20; and ivabradine 0.5 mg/kg, 104 ± 11). Heart rate (min(-1)) was still reduced (P < 0.05) 12 h after ivabradine (0.3 mg/kg; 128 ± 18 and 0.5 mg/kg; 124 ± 16) compared to placebo (141 ± 21). The tachycardic response to acoustic startle was significantly (P < 0.01) blunted at all 3 doses of ivabradine. Myocardial oxygen consumption estimated by the rate-pressure product was significantly reduced (P < 0.05) for all doses of ivabradine. No effect of ivabradine on systolic, diastolic, and mean blood pressure was identified and no clinically discernable side effects were observed. CONCLUSION: These findings indicate that a single oral dose of ivabradine predictably lowers heart rate, blunts the chronotropic response to stress, and is clinically well tolerated in healthy cats. This makes ivabradine potentially interesting in the treatment of feline heart disease where ischemia is of pathophysiologic importance.

Expression of P2X and P2Y receptors in the intramural parasympathetic ganglia of the cat urinary bladder.

The distribution and function of P2X and P2Y receptor subtypes were investigated on intact or cultured intramural ganglia of the cat urinary bladder by immunocytochemistry and calcium-imaging techniques, respectively. Neurons were labeled by all seven P2X receptor subtype antibodies and antibodies for P2Y(2), P2Y(4), P2Y(6), and P2Y(12) receptor subtypes with a staining intensity of immunoreactivity in the following order: P2X(3)=P2Y(2)=P2Y(4)=P2Y(6)=P2Y(12)>P2X(1)=P2X(2)=P2X(4)>P2X(5)=P2X(6)=P2X(7). P2Y(1) receptor antibodies labeled glial cells, but not neurons. P2X(3) and P2Y(4) polyclonal antibodies labeled approximately 95 and 40% of neurons, respectively. Double staining showed that 100, 48.8, and 97.4% of P2X(3) receptor-positive neurons coexpressed choline acetyl transferase (ChAT), nitric oxide synthase (NOS), and neurofilament 200 (NF200), respectively, whereas 100, 59.2, and 97.6% of P2Y(4) receptor-positive neurons coexpressed ChAT, NOS, and NF200, respectively. Application of ATP, alpha,beta-methylene ATP, and uridine triphosphate elevated intracellular Ca(2+) concentration in a subpopulation of dissociated cultured cat intramural ganglia neurons, demonstrating the presence of functional P2Y(4) and P2X(3) receptors. This study indicates that P2X and P2Y receptor subtypes are expressed by cholinergic parasympathetic neurons innervating the urinary bladder. The neurons were also stained for NF200, usually regarded as a marker for large sensory neurons. These novel histochemical properties of cholinergic neurons in the cat bladder suggest that the parasympathetic pathways to the cat bladder may be modulated by complex purinergic synaptic mechanisms.