Sensitization of pelvic nerve afferents and mast cell infiltration in the urinary bladder following chronic colonic irritation is mediated by neuropeptides

Abstract

Irritable bowel syndrome and interstitial cystitis frequently overlap. We have shown that acute colitis sensitizes urinary bladder afferents to both mechanical and chemical stimuli and that chronic colitis similarly produces neurogenic cystitis. We hypothesize that chronic irritation of the colon releases neuropeptides from bladder afferents, leading to receptor sensitization and neurogenic inflammation. Female Sprague-Dawley rats received intrarectal trinitrobenzenesulfonic acid (TNBS) or vehicle 3 days following either systemic capsaicin (CP) pretreatment or vehicle. Ten days later, action potentials of single-unit pelvic C-fiber afferents with receptive fields in the bladder were recorded under urethane anesthesia during graded bladder distensions (UBD) or intravesical capsaicin (vCP) administration. In controls, UBD increased bladder afferent firing in proportion to intravesical pressure. At intravesical pressures of 30 mmHg and above, the percent increase in afferent firing was significantly accentuated following TNBS compared with controls (1,222 +/- 176 vs. 624 +/- 54%, P< 0.01). The response to vCP was also enhanced (4,126 +/- 775 vs. 1,979 +/- 438%, P < 0.01). Systemic depletion of neuropeptides from sensory nerves abolished these effects. Histological examination of the bladders revealed an increase in mast cell density in TNBS-treated animals compared with controls (18.02 +/- 1.25 vs. 3.11 +/- 0.27 mast cells/x100 field, P < 0.01). This effect was significantly ameliorated with CP (10.25 +/- 0.95, P < 0.5 vs. TNBS-treated animals). In summary, chronic colonic irritation in the rat sensitizes urinary bladder afferents to noxious stimuli and causes mast cell infiltration in the bladder. Depletion of neuropeptides from sensory afferents diminishes these effects, suggesting they play an important role.

Organ cross talk modulates pelvic pain

“…There is a growing literature demonstrating "cross talk" between the bladder and the colon at the level of neural signaling (34,35), and this neuronal cross talk likely also involves the uterus (41). To test the possible role of such cross talk in the development of pelvic pain behavior, we also assessed pelvic sensitivity to mechanical stimuli following instillation of 2% lidocaine into the colon or uterus.…”

“…For example, mustard oil administered to the uterine horn or colon in female rats induced vascular permeability in the bladder consistent with inflammation at a site distinct from the inflammatory stimulus (41). This cross talk is at least partially bidirectional, because bladder irritation also sensitized the colon to distension stimuli (28), and this noxious effect can be mediated by either chemical or mechanical stimuli (11,34,35). It is not known whether neurogenic cystitis also involves cross talk, but these previous findings suggest that organ cross talk may be exploited for therapeutic approaches to pelvic pain.…”

Acute colonic inflammation triggers detrusor instability via activation of TRPV1 receptors in a rat model of pelvic organ cross-sensitization

“…Our previous findings showed that intracolonic application of RTX can cause massive release of substance P and calcitonin gene-related peptide from the bladder afferent terminals leading to the development of a neurogenic bladder over a period of time (34). Ustinova and colleagues (45) determined that chronic colonic irritation sensitized urinary bladder afferents to noxious stimuli and caused mast cell infiltration in the bladder. The latter effects were reversed by systemic administration of the TRPV1 agonist capsaicin, suggesting the involvement of TRPV1 receptors in colon-bladder cross talk.…”

“…Previous animal studies have established a correlation between structural pathophysiological changes in the directly affected pelvic organs and secondary dysfunctions developed in adjacent pelvic structures (9,27,28,36). It has been determined that colonic inflammation causes hyperactivity of bladder afferent fibers (44), hyperexcitability of bladder projecting sensory (27, 28) and spinal (38) neurons, increased release of proinflammatory neuropeptides in the urinary bladder (34,45), and changes in the detrusor contractility (32). However, the exact pathways of transmission of nociceptive information from the inflamed colon to the urinary bladder as well as receptors and molecules activated during this transmission remain elusive.…”

Inflammation and Chronic Pelvic Pain: A Biological Trigger for Depression in Women?

“…Of note, women experiencing CPP often exhibit overlapping symptoms of BPS/IC and IBS [76]. Much of this overlap can be attributed to central and peripheral neural mechanisms of pelvic organ cross-sensitization [77][78][79]. However, the juxtaposition of SP-positive nerve fibers and MCs [80] may play an important role in pelvic organ cross-sensitization by amplifying afferent signaling.…”