Abstract
Co-morbidity of bladder, bowel, and non-specific pelvic pain symptoms is highly prevalent in women. Little evidence is present on modulation of pelvic pain syndromes by sex hormones, therefore, the objective of this study was to clarify the effects of hormonal fluctuations within the estrous cycle on regulatory neuropeptides in female rats using a model of neurogenic bladder dysfunction. The estrous cycle in female rats (Sprague-Dawley, 230–250 g) was assessed by vaginal smears and weight of uterine horns. Neurogenic bladder dysfunction was induced by a single inflammatory insult to the distal colon. Protein expression of calcitonin gene related peptide (CGRP), substance P (SP), nerve growth factor (NGF), and brain derived neurotrophic factor (BDNF) in the pelvic organs, sensory ganglia and lumbosacral spinal cord was compared in rats in proestrus (high estrogen) vs diestrus (low estrogen). Under normal physiological conditions, concentration of SP and CGRP was similar in the distal colon and urinary bladder during all phases of the estrous cycle, however, acute colitis induced a significant up-regulation of CGRP content in the colon (by 63%) and urinary bladder (by 54%, p≤0.05 to control) of rats in proestrus. These changes were accompanied by a significant diminution of CGRP content in L6-S2 DRG after colonic treatment, likely associated with its release in the periphery. In rats with high estrogen at the time of testing (proestrus), experimental colitis caused a significant up-regulation of BDNF colonic content from 26.1±8.5 pg/ml to 83.4±32.5 pg/ml (N = 7, p≤0.05 to control) and also induced similar effects on BDNF in the urinary bladder which was also up-regulated by 5-fold in rats in proestrus (p≤0.05 to respective control). Our results demonstrate estrous cycle dependent fluctuations of regulatory neuropeptides in the lower urinary tract upon colon-bladder cross-sensitization, which may contribute to pain fluctuations in female patients with neurogenic bladder pain.
Highlights
Chronic pelvic pain (CPP) affects up to 2.5 million women [1] and is more common in women than migraine or asthma [2,3]
We previously established that Substance P (SP) and calcitonin gene-related peptide (CGRP) contribute to long-lasting sensitization of neural pathways innervating the lower urinary tract (LUT) after transient inflammatory insult to the distal colon, thereby, causing neurogenic bladder dysfunction [9]
Phase of the Estrous Cycle and Effects of Colitis The phases of the estrous cycle were followed for 3 cycles in all female rats with an average duration of the cycle from 4 to 5 days
Summary
Chronic pelvic pain (CPP) affects up to 2.5 million women [1] and is more common in women than migraine or asthma [2,3]. Recent clinical and translational studies provide evidence that co-occurrence of bladder, bowel and nonspecific pelvic pain symptoms may be due to development of crosssensitization in the pelvis via neural mechanisms [5,6,7] and on the possible modulation of such pain by sex hormones [8]. Our previous animal data from males established an association between inflammation in the pelvis, release of pro-inflammatory neuropeptides from pelvic afferents, and development of pelvic organ cross-sensitization [9,10]. Release of SP and CGRP from afferent terminals leads to the development of neurogenic inflammation in the affected viscera associated with degranulated mast cells, local plasma extravasation and arteriolar vasodilation [13]. We previously established that SP and CGRP contribute to long-lasting sensitization of neural pathways innervating the lower urinary tract (LUT) after transient inflammatory insult to the distal colon, thereby, causing neurogenic bladder dysfunction [9]
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