Bladder Dysfunction and Altered Somatic Sensitivity in PACAP ^−/− Mice

Abstract

Purpose Pituitary adenylate cyclase activating polypeptide (PACAP) and receptors are expressed in micturition pathways. Studies demonstrated roles for PACAP in detrusor smooth muscle contraction, facilitating ATP release from urothelium and PACAP antagonism reduced cyclophosphamide-induced bladder hyperreflexia. Materials and Methods PACAP contributions to micturition and somatic sensation were studied in PACAP knockout (PACAP−/−), littermate heterozygote (PACAP+/−) and wildtype (WT) mice using conscious cystometry with continuous intravesical saline or acetic acid (AA; 0.5%) instillation, urination patterns, somatic sensitivity testing of hindpaw and pelvic region with calibrated von Frey filaments and morphological assessments of urinary bladder. Results PACAP−/− mice exhibit increased bladder mass with fewer but larger urine spots. In PACAP−/− mice, the lamina propria and detrusor smooth muscle are significantly thicker whereas the urothelium is unchanged. PACAP−/− mice exhibit increased bladder capacity, void volume (VV) and longer intercontraction interval (ICI) with significantly increased detrusor contraction duration and large residual volume. WT mice respond to AA (0.5%) with a reduction in VV and a decreased ICI whereas PACAP+/− and PACAP−/− mice do not respond. PACAP−/− mice are less responsive to somatic stimulation. PACAP+/− also exhibit bladder dysfunction and somatic and visceral sensory abnormalities but to a lesser degree. Conclusions PACAP gene disruption contributes to changes in bladder morphology, bladder function and somatic and visceral hypoalgesia.

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

“…Similarly, increases in peripheral sensitivity to mechanical stimuli using von Frey filament application to the hindpaw are seen following CYP-induced cystitis in rodents (73). Therefore, increases in hindpaw and pelvic referred somatic sensitivity in the present study are similar to results seen in animal models of IC/BPS (45,61,67).…”

Activation of cannabinoid receptor 2 inhibits experimental cystitis

“…Stimulus-related retraction of the tested paw was considered a withdrawal response, and the 50% paw withdrawal threshold was determined by the nonparametric method of Dixon (10). Previous studies have reported enhanced mechanical sensitivity of both the hind paws and pelvic region of mice in experimental cystitis (48,66,74) and similar results are reported, regardless of the area tested (48,66).…”

Remote control of renal physiology by the intestinal neuropeptide pigment-dispersing factor in Drosophila

“…the ureter control the flow of urine into the terminal portion of the digestive tract (29,30) in a manner analogous to the VPAC2R + detrusor muscle of the mammalian bladder. Abnormal fluid regulation has also been described in mice lacking VIP or PACAP (40,42,43), so it will be of interest to establish if PDF signaling has related in vivo roles in flies. The presence of VIP/PACAP immunoreactivity in neural fibers of the lower urinary tract of mammals suggests a local, transmitter-like action on the excretory muscle receptors (12), and VIP is generally believed to act as a local neurotransmitter rather than as a circulating hormone (44,45).…”