Cross-talk and sensitization of bladder afferent nerves

Elena E. Ustinova, Matthew O. Fraser, Michael A. Pezzone
Neurourology and urodynamics · 2009 · vol. 29(1) , pp. 77–81 · doi:10.1002/nau.20817 · PMID:20025032 · PMC2805190 · W2073876637
Review OA: bronze CC0 ⤵ 8 in-corpus citations
📄 Open PDF Full text JSON View on OpenAlex View on PubMed View at publisher
⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-09 ⓘ

Intracolonic irritation bi-directionally sensitizes bladder afferent nerves to chemical and mechanical stimuli in an animal model, likely mediated by neuropeptides and mast cells.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

⚙ AI-generated deep summary by qwen3.7-flash, 2026-10-10 · read from full text ⓘ

This study investigates the neural mechanisms underlying cross-sensitization between pelvic organs using rat and mouse models to map afferent nerve pathways. Researchers identified dichotomizing neurons in dorsal root ganglia that simultaneously innervate both the bladder and colon, demonstrating that acute or subacute colonic irritation sensitizes bladder afferents and induces mast cell infiltration. The findings indicate that pre-existing convergent neural circuits facilitate neurogenic inflammation and functional changes in non-irritated organs through antidromic neuropeptide release. Relevance to endometriosis: listed as one indication for GnRH antagonists, though the paper's main focus is uterine fibroids.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Abstract

The coordination of pelvic physiologic function requires complex integrative sensory pathways that may converge both peripherally and/or centrally. Following a focal, acute irritative or infectious pelvic insult, these same afferent pathways may produce generalized pelvic sensitization or cross-sensitization as we show bi-directionally for the bladder and bowel in an animal model. Single unit bladder afferent recordings following intracolonic irritation reveal direct sensitization to both chemical and mechanical stimuli that's dependent upon both intact bladder sensory (C-fiber) innervation and neuropeptide content. Concurrent mastocytosis (preponderantly neurogenic) likely plays a role in long-term pelvic organ sensitization via the release of nociceptive and afferent-modulating molecules. Prolonged pelvic sensitization as mediated by these convergent and antidromic reflexive pathway may likewise lead to chronic pelvic pain and thus the overlap of chronic pelvic pain disorders.
Full text 14,445 characters · extracted from pmc-nxml · 6 sections · click to expand

A

Pre-existing afferent pathways and associated neuropeptide release from C-fibers appear to play important roles in an animal model of acute (1 hr) and sub-acute (10 days) pelvic organ cross-sensitization. The chronic effects of cross-afferent stimulation (colon→bladder) on physiologic function of the urinary bladder and vice versa have not been previously studied. Chronic morphologic changes in sensory and motor neurons innervating the bladder and alterations in the number and distribution of bladder mast cells (MCs) were noted following chemical, immune, and mechanical irritation of the bladder [ 38 ]. Neuroplasticity observed in these models of direct bladder irritation could explain long-term symptoms, including pain, seen even after the resolution of bladder inflammation [ 38 ], and one may likewise hypothesize that this neuroplasticity may not necessarily be limited to the bladder itself and may involve other pelvic organs, as suggested in pelvic cross-sensitization studies [ 8 , 9 , 32 , 33 ]. With continued stimulation of this cross-organ neural circuitry, physiologic changes could develop not only in the affected pelvic organ, but also in other pelvic organs with convergent afferent input that could lead to development and overlap of CPP disorders [ 32 ]. A putative role of MCs in IC [ 39 ], IBS [ 40 – 42 ], and other disorders characterized by hyperalgesia and neurogenic inflammation [ 43 ] has been implicated. Not only do MCs contain a formidable armamentarium of nociceptive molecules, including adenosine phosphates, bradykinin, histamine, leukotrienes, potassium, lymphokines, tumor necrosis factor (TNF), and prostaglandins [ 44 ], their close apposition to nerve fibers in the human gastrointestinal tract [ 45 , 46 ] and urinary bladder [ 47 ] also provides anatomical evidence supporting MC-mediated modulation of afferent nerve function. Lastly, and also supporting our hypotheses, CNS-induced neurogenic cystitis following pseudorabies virus infection was also associated with bladder mast cell degranulation in the rat [ 48 ]. To further explore this hypothesis, we evaluated the physiologic effects of colonic irritation on urinary bladder function 60–90 days after TNBS-induced colonic irritation (ie, during the resolution phase of this model) [ 49 ]. Bladder MCs were enumerated, and those activated (containing <20% of cellular staining) were quantified to begin to identify histologic and biochemical changes in afferent and end-organ pathways that may be responsible for neurogenic inflammation and afferent cross-sensitization. TNBS was instilled into the colons of another group of rats, and RT-PCR was used to quantify abundance of mRNA for stem-cell factor (SCF) or MC growth factor and nerve growth factor (NGF), a neurotrophic factor and also an MC-stimulatory factor that acts synergistically with SCF [ 50 – 42 ] in urinary bladders and L6-S1 DRG (corresponding to LS-afferent input from the bladder and distal colorectum of the rat). Urine voiding volume was reduced (p<0.005), and voiding frequency was increased (p<0.05), both by ≈50%, after intra-rectal TNBS and was consistent with chronic irritative micturition. Although total MC counts were not statistically increased as in the sub-acute phase of this model (10 days), both the percentage and density of activated bladder MCs were significantly increased (p<0.05). SCF and NGF mRNA expression were both increased 2-fold in the bladder (p<0.005 and p<0.01, compared to controls), but there were no significant changes in the L6-S1 DRG. Thus, chronic cystitis in the rat, as evidenced by changes in micturition and recruitment of activated MCs to the bladder wall, was observed during the resolution of TNBS colitis. These changes, which appear to be maintained with time, are clearly a consequence of antidromically stimulated convergent pelvic afferent pathways and the consequential expression of neurotrophic factors in the target (uninsulted) organ (bladder).

Neural

The development of pelvic organ cross-sensitization requires cross-afferent stimulation in the pelvis. Afferent information from the major pelvic organs, such as the bladder, colorectum, and uterus, is conducted through hypogastric, splanchnic, pelvic, and pudendal nerves to cell bodies in thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia (DRG) [ 18 ]. Typically, noxious prodromic (peripheral→central) noxious afferent stimulation from an irritated pelvic organ leads to antidromic (central→peripheral) afferent stimulation and co-sensitization of another “non-irritated” pelvic organ. These reflexive pathways may occur locally (peripherally) via axon collaterals (dichotomizing afferents), in the spinal cord (dorsal root reflexes), and/or in the central nervous system (CNS) [ 19 ]. Consequently, neurogenic sensitization or neurogenic “inflammation” via antidromic pathways may produce functional changes in the uninsulted organ with no or little evidence of an organic etiology.

Summary

Colonic irritation and cross-afferent pelvic stimulation lead to bladder cross-sensitization, as evidenced by changes in physiology, mast cell histology, and neurotrophin expression. Bladder afferent sensitization is a key component in this process, and there is substantial evidence that the mast cell is an important intermediary. Mast-cell migration, activation, and sensitization, expression of multiple neurotrophic, mast-cell stimulatory, and afferent-sensitizing factors collectively influence the physiology of the indirectly affected pelvic organ (ie, even in the absence of direct irritation). Future studies are needed to further identify additional putative pathways involved in induction, maintenance, reactivation, and perhaps overlap of CPP disorders.

Evidence

Overlapping CPP disorders could originate peripherally via axonal collaterals (the simplest reflexive afferent pathway) through which a single primary afferent supplies two structures (dichotomizing afferent). Dichotomizing neurons within the DRG were first proposed by Sinclair [ 20 ] and have seen been shown in several species to range from 0.5% to 15% of all afferent nerve fibers [ 21 ]. Supporting their role in referred sacral pain via dichotomizing sacral afferents, there are 2.3 times as many peripheral nerve fibers as there are cell bodies in the corresponding sacral DRG [ 22 ]. Thus, irritation of one pelvic organ may lead to referred pain and/or neurogenic inflammation in another by means of antidromic activation of afferent terminals emanating from the same DRG neuron. Using fluorescent cholera toxin subunit B (CTB) conjugates to identify potential cross-organ sensitizing that dichotomizes DRG neurons in the pelvis, we performed concomitant retrograde labeling of both urinary bladder and distal colon afferents in Sprague-Dawley rats and C57Bl/6 mice [ 23 ]. In preparation for immunohistochemical localization of labeled afferents, animals were perfused 4–5 days after subserosal organ injections, and T10-S2 DRG were removed, sectioned, and analyzed using confocal microscopy. CTB-positive bladder afferent fibers in the rat were nearly 3 times more numerous than those from the distal colon, while in the mouse, each organ was equally represented. In both species, the majority of colon and bladder afferent fibers (both single- and dual-organ projections, the majority of which were single-organ projections) projected from LS ganglia and to a lesser extent, from TL ganglia. In the rat, 17% of the total CTB-positive neurons were retrogradely labeled from both organs, with 11% localized in the TL, 6% in the LS, and 0.8% in the thoracic (TH) ganglia (dual-organ projections were more prominent in the TL ganglia). In the mouse, 21% of the total CTB-positive neurons were dually-labeled, with 12% localized in the LS, 4% in the TH, and 4% in the TL ganglia. These findings support the existence of dichotomizing pelvic afferents that provide a pre-existing neuronal network for potential immediate and sustained pelvic organ cross-sensitization, which may play a role in CPP disorders.

Depletion

Given the findings in our acute afferent studies, we proposed that continued pelvic cross-afferent stimulation would result in continued antidromic release of neuropeptides from afferent endings and lead to receptor sensitization and neurogenic “inflammation.” To test this hypothesis, we recorded single-unit bladder C-fiber activity from fine filaments of the pelvic nerve in urethane-anesthetized Sprague-Dawley female rats and assessed their responsiveness to mechanical (UBD) and chemical (intravesical CP, bradykinin, or substance P) stimulation 10 days after intracolonic administration of TNBS (subacute phase) or vehicle [ 36 ]. To eliminate the contribution of C-fibers and their associated neuropeptides, some animals were pretreated systemically with CP 3 days prior to colonic irritation [ 37 ]. UBD increased bladder afferent firing in proportion to intravesical pressure in control animals. At intravesical pressures of 30 mm Hg and above, the percent increase in afferent firing was significantly increased after TNBS compared with animals that did not receive TNBS (1222 ± 176% vs. 624 ± 54%, respectively, p<0.01). The response to intravesical CP was also increased after vs. before intracolonic TNBS (4126 ± 775% vs. 1979 ± 438%, respectively, p<0.01). Systemic depletion of neuropeptides from sensory nerves with CP prior to TNBS abolished these effects. Histologic examination of the bladders revealed a dramatic increase in mast-cell density in TNBS-treated animals compared to controls (18.02 ± 1.25 vs. 3.11 ± 0.27 mast cells per 100× field, respectively, p<0.01). Bladder mast cell (MC) numbers in TNBS-treated animals were significantly decreased by systemic CP pre-treatment (10.25 ± 0.95/100x field, p<0.05 vs. TNBS-treated control animals). These findings confirm that subacute colonic irritation (10 days post-TNBS) in the rat sensitizes urinary bladder afferents to noxious stimuli and causes mast-cell infiltration in the bladder. Inhibition of C-fiber afferent function diminished these effects, supporting their role in the effect of TNBS-induced colitis and neurogenic cystitis.

Single Unit

Acute colitis can increase the excitability of bladder nociceptive neurons, as measured by enhanced responses to capsaicin (CP) and accentuated sodium currents in dispersed bladder DRG cells [ 34 ]. To directly test the hypothesis that colonic irritation can alter the mechano-and chemo-sensitive properties of urinary bladder afferents, we recorded single-unit bladder C-fiber activity from fine filaments of the pelvic nerve in urethane-anesthetized Sprague-Dawley female rats, and assessed their responsiveness to bladder distension and intravesical CP, bradykinin, or substance P stimulation before and 1 hour after (acute) intracolonic administration of trinitrobenzenesulfonic acid (TNBS) [ 33 ]. Colonic irritation increased the resting firing rate of bladder afferents 2-fold (1.0 ± 0.2 vs. 0.49 ± 0.2 imp/sec, respectively, p<0.05). Moreover, a greater percentage of bladder afferents responded to low pressure urinary bladder distensions (UBDs, 10–20 mm Hg) 1 hour after vs before TNBS administration (73% vs. 27%, respectively, p<0.05), and this observation was consistent with lowered afferent sensory thresholds or activation of silent nociceptors as proposed previously [ 35 ]. Although the magnitude of the afferent response to UBD was unchanged at low pressures, the response was greatly enhanced at pressures of 30 mm Hg and above (2.36 ± 0.56 vs. 8.55 ± 0.73 imp/sec, respectively, p<0.05). Responses to CP, bradykinin, and Substance P were also significantly increased after TNBS, and all responses were blocked by bladder denervation [ 33 ]. These studies confirm that acute colonic irritation with TNBS directly sensitizes the mechano- and chemo-receptive properties of urinary bladder C-fibers traveling within the pelvic nerve, and shed further light on our initial observations regarding cross-organ sensitization [ 32 ]. We propose that such cross-organ afferent pathways may originate centrally via spinal or supra-spinal circuits (including spinal antidromic dorsal root reflexes), and/or peripherally directly from the colon via antidromic axon reflexes from a single dichotomizing primary afferent supplying two structures (prespinal convergence).

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: pmc-nxml ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

chronic_pelvic_pain

MeSH descriptors

Afferent Pathways Colon Cystitis, Interstitial Neurons, Afferent Pelvic Pain Urinary Bladder Action Potentials Afferent Pathways Afferent Pathways Afferent Pathways Animals Chronic Disease Colon Cystitis, Interstitial Cystitis, Interstitial Cystitis, Interstitial Disease Models, Animal Humans Mast Cells Mast Cells

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (55)

Cited by (6)

Source provenance

openalex
last seen: 2026-06-10T17:14:06.276822+00:00
pubmed
last seen: 2026-10-08T21:07:11.085580+00:00
License: CC0 · commercial use OK