Protease-activated receptor (PAR(2)) is expressed by nociceptive neurons and activated during inflammation by proteases from mast cells, the intestinal lumen, and the circulation. Agonists of PAR(2) cause hyperexcitability of intestinal sensory neurons and hyperalgesia to distensive stimuli by unknown mechanisms. We evaluated the role of the transient receptor potential vanilloid 4 (TRPV4) in PAR(2)-induced mechanical hyperalgesia of the mouse colon. Colonic sensory neurons, identified by retrograde tracing, expressed immunoreactive TRPV4, PAR(2), and calcitonin gene-related peptide and are thus implicated in nociception. To assess nociception, visceromotor responses (VMR) to colorectal distension (CRD) were measured by electromyography of abdominal muscles. In TRPV4(+/+) mice, intraluminal PAR(2) activating peptide (PAR(2)-AP) exacerbated VMR to graded CRD from 6-24 h, indicative of mechanical hyperalgesia. PAR(2)-induced hyperalgesia was not observed in TRPV4(-/-) mice. PAR(2)-AP evoked discharge of action potentials from colonic afferent neurons in TRPV4(+/+) mice, but not from TRPV4(-/-) mice. The TRPV4 agonists 5',6'-epoxyeicosatrienoic acid and 4alpha-phorbol 12,13-didecanoate stimulated discharge of action potentials in colonic afferent fibers and enhanced current responses recorded from retrogradely labeled colonic dorsal root ganglia neurons, confirming expression of functional TRPV4. PAR(2)-AP enhanced these responses, indicating sensitization of TRPV4. Thus TRPV4 is expressed by primary spinal afferent neurons innervating the colon. Activation of PAR(2) increases currents in these neurons, evokes discharge of action potentials from colonic afferent fibers, and induces mechanical hyperalgesia. These responses require the presence of functional TRPV4. Therefore, TRPV4 is required for PAR(2)-induced mechanical hyperalgesia and excitation of colonic afferent neurons.
Several recent reports have indicated an increased prevalence of gallstones in association with pregnancy. If these reports are true, the early puerperium should be a favorable time to detect the disease in its initial stages and follow its natural course. Accordingly, the gallbladder was examined by ultrasound in 980 women during the immediate postpartum period and in 150 nulliparous, age-matched healthy volunteers. Gallstones were detected in 12.2% of the puerperal women and in 1.3% of the control group. In 70 patients who had stones in a functioning gallbladder, 22 (31%) had had attacks of biliary colic. The history of pain was more common in patients with stones greater than 10 mm in diameter. Forty-one women with small stones (< 10 mm) were followed clinically and ultrasonographically for between 6 and 24 (mean = 8.7) mo. All remained pain-free, and in twelve subjects (29%) the stones disappeared. Gallbladder bile was examined in 11 normal volunteers (controls) immediately after delivery and in 19 women with small stones 39 +/- 6 days postpartum. Bile was saturated with cholesterol in the controls and was unsaturated in patients with gallstones. We conclude that in our population pregnancy is a very important pathogenetic factor favoring gallstone formation. Attacks of biliary colic appear early and frequently in young Chilean women with this disease. Unexplained disappearance of small stones frequently occurs: in some cases it is likely to be the result of spontaneous dissolution because bile becomes unsaturated within a few weeks of delivery.
Our data demonstrate that transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity associated with cystitis.
The urinary nerve growth factor-to-creatinine and brain-derived neurotrophic factor-to-creatinine ratios are increased in patients with overactive bladder. These findings may have pathophysiological and clinical implications.
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