A Model of Neural Cross-Talk and Irritation in the Pelvis: Implications for the Overlap of Chronic Pelvic Pain Disorders
2005; Elsevier BV; Volume: 128; Issue: 7 Linguagem: Inglês
10.1053/j.gastro.2005.03.008
ISSN1528-0012
AutoresMichael A. Pezzone, Ruomei Liang, Matthew O. Fraser,
Tópico(s)Urinary Bladder and Prostate Research
ResumoBackground & Aims: Irritable bowel syndrome, interstitial cystitis, and other chronic pelvic pain (CPP) disorders often occur concomitantly. Neural cross-talk may play a role in the overlap of CPP disorders via the convergence of pelvic afferents. We investigated the hypothesis that afferent irritation of one pelvic organ may adversely influence and sensitize another via neural interactions. Methods: We measured pelvic organ smooth muscle and striated muscle reflexes during micturition and colorectal distention (CRD) in urethane-anesthetized rats. The effects of acute cystitis on distal colonic sensory thresholds to CRD and the effects of acute colonic irritation on micturition parameters were assessed. Results: External urethral sphincter (EUS) electromyography (EMG) was typical for the rat, with phasic firing during micturition. External anal sphincter EMG also showed phasic firing during micturition in synchrony with EUS activity but, in addition, showed both tonic bursts and phasic firing independent of EUS activity. Before bladder irritation, graded CRDs to 40 cm H2O produced no notable changes in abdominal wall EMG activity. Following acute bladder irritation, dramatic increases in abdominal wall EMG activity in response to CRD were observed at much lower distention pressures, indicating colonic afferent sensitization. Analogously, following acute colonic irritation, bladder contraction frequency increased 66%, suggesting sensitization of lower urinary tract afferents. Conclusions: We report compelling evidence of bidirectional cross-sensitization of the colon and lower urinary tract in a novel experimental model. This cross-sensitization may account for the substantial overlap of CPP disorders; however, further studies are needed to fully characterize these pathways. Background & Aims: Irritable bowel syndrome, interstitial cystitis, and other chronic pelvic pain (CPP) disorders often occur concomitantly. Neural cross-talk may play a role in the overlap of CPP disorders via the convergence of pelvic afferents. We investigated the hypothesis that afferent irritation of one pelvic organ may adversely influence and sensitize another via neural interactions. Methods: We measured pelvic organ smooth muscle and striated muscle reflexes during micturition and colorectal distention (CRD) in urethane-anesthetized rats. The effects of acute cystitis on distal colonic sensory thresholds to CRD and the effects of acute colonic irritation on micturition parameters were assessed. Results: External urethral sphincter (EUS) electromyography (EMG) was typical for the rat, with phasic firing during micturition. External anal sphincter EMG also showed phasic firing during micturition in synchrony with EUS activity but, in addition, showed both tonic bursts and phasic firing independent of EUS activity. Before bladder irritation, graded CRDs to 40 cm H2O produced no notable changes in abdominal wall EMG activity. Following acute bladder irritation, dramatic increases in abdominal wall EMG activity in response to CRD were observed at much lower distention pressures, indicating colonic afferent sensitization. Analogously, following acute colonic irritation, bladder contraction frequency increased 66%, suggesting sensitization of lower urinary tract afferents. Conclusions: We report compelling evidence of bidirectional cross-sensitization of the colon and lower urinary tract in a novel experimental model. This cross-sensitization may account for the substantial overlap of CPP disorders; however, further studies are needed to fully characterize these pathways. Chronic pelvic pain (CPP) encompasses a group of debilitating disorders primarily affecting women of reproductive age. Characterized by pain involving the pelvic cavity (irritable bowel syndrome [IBS] and interstitial cystitis [IC]) and/or the pelvic floor (levator ani syndrome, urethral syndrome, prostatodynia, vulvodynia, and orchialgia),1Wesselmann U. Neurogenic inflammation and chronic pelvic pain.World J Urol. 2001; 19: 180-185Crossref PubMed Google Scholar CPP affects as many as 15% of women in both the United States and the United Kingdom.2Mathias S.D. Kuppermann M. Liberman R.F. Lipschutz R.C. Steege J.F. Chronic pelvic pain prevalence, health-related quality of life, and economic correlates.Obstet Gynecol. 1996; 87: 321-327Crossref PubMed Scopus (857) Google Scholar, 3Zondervan K. Yudkin P.L. Vessey M.P. Jenkinson C.P. Dawes M.G. Barlow D.H. Kennedy S.H. The community prevalence of chronic pelvic pain in women and associated illness behavior.Br J Gen Pract. 2001; 51: 541-547PubMed Google Scholar Because the colorectum and urinary bladder are two of the larger pelvic organs and because their functions are an integral part of daily, conscious, physiologic pelvic activity, it is perhaps not surprising that IBS and IC, analogous disorders of pelvic visceral pain and urgency, are two of the more common manifestations of CPP. IBS, an intestinal disorder characterized by chronic or recurrent lower abdominal pain or discomfort associated with altered stool consistency and frequency,4Thompson W.G. Longstreth G.F. Drossman D.A. Heaton K.W. Irvine E.J. Muller-Lissner S.A. Functional bowel disorders and functional abdominal pain.in: Drossman D.A. Corazziari E. Talley N. Thompson W.G. Whitehead W.E. The functional gastrointestinal disorders. 2nd ed. Degnon Associates, McLean VA2000: 351-375Google Scholar is the most common gastrointestinal cause of CPP, affecting 50% of such women presenting to gynecologic clinics.5Hogston P. Irritable bowel syndrome as a cause of chronic pain in women attending a gynaecology clinic.Br Med J. 1987; 294: 934-935Crossref PubMed Scopus (49) Google Scholar, 6Prior A. Wilson K. Whorwell P.J. Faragher E.B. Irritable bowel syndrome in the gynecological clinic Survey of 798 new referrals.Dig Dis Sci. 1989; 34: 1820-1824Crossref PubMed Scopus (109) Google Scholar, 7Walker E.A. Katon W.J. Jemelka R. The prevalence of chronic pelvic pain and irritable bowel in two university clinics.J Psychosom Obstet Gynaecol. 1991; 12s: 65-70Google Scholar, 8Walker E.A. Gelfand A.N. Gelfand M.D. Green C. Katon W.J. Chronic pelvic pain and gynecological symptoms in women with irritable bowel syndrome.J Psychosom Obstet Gynaecol. 1996; 17: 39-46Crossref PubMed Scopus (105) Google Scholar Patients with IBS, 70% of whom are women, incur 74% more direct health care costs than those without IBS and have more physician visits for both gastrointestinal and nongastrointestinal symptoms.9Drossman D.A. Li Z. Andruzzi E. Temple R.D. Talley N.J. Thompson W.G. Whitehead W.E. Janssens J. Funch-Jensen P. Corazziari E. Richter J.E. Koch G.G. U.S. householder survey of functional gastrointestinal disorders Prevalence, sociodemography, and health impact.Dig Dis Sci. 1993; 38: 1569-1580Crossref PubMed Scopus (1971) Google Scholar, 10Levy R.L. Von Korff M. Whitehead W.E. Stang P. Saunders K. Jhingran P. Barghout V. Feld A.D. Costs of care for irritable bowel syndrome patients in a health maintenance organization.Am J Gastroenterol. 2001; 96: 3122-3129Crossref PubMed Google Scholar, 11Longstreth G.F. Wilson A. Knight K. Wong J. Chiou C.F. Barghout V. Frech F. Ofman J.J. Irritable bowel syndrome, health care use, and costs a U.S. managed care perspective.Am J Gastroenterol. 2003; 98: 600-607Crossref PubMed Scopus (257) Google Scholar IBS alone results in an estimated $8 billion in direct medical costs annually.12Talley N.J. Gabriel S.E. Harmsen W.S. Zinsmeister A.R. Evans R.W. Medical costs in community subjects with irritable bowel syndrome.Gastroenterology. 1995; 109: 1736-1741Abstract Full Text PDF PubMed Scopus (439) Google Scholar IC or painful bladder syndrome, a CPP disorder that afflicts women almost exclusively, is characterized by unpleasant urinary symptoms such as urinary frequency, urgency, nocturia, and, most notably, pain (suprapubic, pelvic, urethral, vaginal, and perineal) related to bladder filling in the absence of active infection or organic disease.13Ratner V. Interstitial cystitis a chronic inflammatory bladder condition.World J Urol. 2001; 19: 157-159Crossref PubMed Scopus (13) Google Scholar, 14Koziol J.A. Epidemiology of interstitial cystitis.Urol Clin North Am. 1994; 21: 7-20PubMed Google Scholar More than 700,000 women in the United States have IC,13Ratner V. Interstitial cystitis a chronic inflammatory bladder condition.World J Urol. 2001; 19: 157-159Crossref PubMed Scopus (13) Google Scholar and associated yearly direct and indirect costs exceed $430 million according to 1982 figures.15Doggweiler R. Blankenship J. MacDiarmid S.A. Review on chronic pelvic pain from a urological point of view.World J Urol. 2001; 19: 160-165Crossref PubMed Scopus (12) Google Scholar Health care costs aside, IC, IBS, and other causes of CPP impact dramatically on quality of life, and their predilection for women also adds to the health burden of this poorly studied population. Although the etiologies of both IBS and IC have been studied extensively (albeit mutually exclusively) and their prevalence is frequently concurrent, few have considered a common underlying mechanism responsible for the development and the overlap of these and other causes of CPP. As many as 40%–60% of patients diagnosed with IBS also exhibit symptoms and fulfill diagnostic criteria for IC; correspondingly, 38% of patients diagnosed with IC also have symptoms and fulfill diagnostic criteria for IBS.6Prior A. Wilson K. Whorwell P.J. Faragher E.B. Irritable bowel syndrome in the gynecological clinic Survey of 798 new referrals.Dig Dis Sci. 1989; 34: 1820-1824Crossref PubMed Scopus (109) Google Scholar, 16Alagiri M. Chottiner S. Ratner V. Slade D. Hanno P.M. Interstitial cystitis unexplained associations with other chronic disease and pain syndromes.Urology. 1997; 49s: 52-57Abstract Full Text PDF Scopus (321) Google Scholar, 17Whorwell P.J. McCallum M. Creed F.H. Roberts C.T. Non-colonic features of irritable bowel syndrome.Gut. 1986; 27: 37-40Crossref PubMed Scopus (426) Google Scholar Furthermore, 26% of patients diagnosed with IC have also been found to have concurrent pain of the vulva or vulvodynia,18Fitzpatrick C.C. DeLancey J.O.L. Elkins T.E. McGuire E.J. Vulvar vestibulitis and interstitial cystitis a disorder of urogenital-derived epithelium?.Obstet Gynecol. 1993; 81: 860-862PubMed Google Scholar and 45% of men with chronic prostatitis or male CPP exhibit pain with bladder filling, a classic feature of IC.19Moldwin R.M. Similarities between interstitial cystitis and male chronic pelvic pain syndrome.Current Urology Reports. 2002; 3: 313-318Crossref PubMed Scopus (56) Google Scholar The high concurrence rate of IBS, IC, and other CPP disorders is therefore substantial and may suggest a common predisposition, a shared etiologic factor, or possible cross-sensitization of pelvic organs. Neural cross-talk in the pelvis, which occurs when afferent activation of one pelvic structure influences efferent output to another, is necessary for the normal regulation of sexual, bladder, and bowel function and is likely mediated by the convergence of sensory pathways in the spinal cord.20Janig W. Koltzenburg M. On the function of spinal primary afferent fibres supplying colon and urinary bladder.J Auton Nerv Syst. 1990; 30: S89-S96Abstract Full Text PDF PubMed Scopus (107) Google Scholar, 21de Groat W.C. Nadelhaft I. Milne R.J. Booth A.M. Morgan C. Thor K. Organization of the sacral parasympathetic reflex pathways to the urinary bladder and large intestine.J Auton Nerv Syst. 1981; 3: 339-350Abstract Full Text PDF Scopus (420) Google Scholar, 22de Groat W.C. Steers W.X. Neuroanatomy and neurophysiology of penile erection.in: Tanagho E.A. Lue T.F. McClure R.D. Contemporary management of impotence and infertility. Williams & Wilkins, Baltimore, MD1988: 3-27Google Scholar, 23de Groat W.C. Booth A.M. Yoshimura N. Neurophysiology of micturition and its modification in animal models of human disease.in: Maggi C.A. The autonomic nervous system. Volume 3. Harwood, London, England1993: 227-290Google Scholar, 24de Groat W.C. Roppolo J.R. Yoshimura N. Sugaya K. Tache Y. Wingate T. Burks T. Neural control of the urinary bladder and colon. CRC, Boca Raton, FL1993: 167-190Google Scholar, 25de Groat W.C. Booth A.M. Neural control of penile erection.in: Maggi C.A. The autonomic nervous system. Volume 3. Harwood, London, England1993: 467-524Google Scholar For example, overlapping central projections of pelvic and pudendal afferents allow integration of somatic and parasympathetic motor activity in the pelvis and facilitate the orchestration of sacral reflexes. Correspondingly, the convergence of afferents from the bladder and bowel is a common feature of visceral interneurons that are believed to mediate vesicosphincteric and colono-sphincteric reflexes and colonovesical cross-inhibitory interactions.26McMahon S.B. Morrison J.F.B. Two groups of spinal interneurones that respond to stimulation of the abdominal viscera of the cat.J Physiol. 1982; 322: 21-34PubMed Google Scholar Because a neural substrate for pelvic organ cross-talk exists under normal conditions, alterations in these neural pathways by disease or injury may play a role in the development of overlapping CPP disorders and pelvic organ cross-sensitization. Previously, no one has adequately investigated the hypothesis that afferent sensitization of one pelvic organ may adversely influence and sensitize the other via direct neuronal connections, reflexes, or changes in central processing. We hypothesized that acute irritation of one pelvic organ could lead to afferent sensitization of another via shared pelvic afferent innervation and/or convergent afferent pathways and that this cross-sensitization could account for an overlap of CPP disorders and result in "referred" pelvic pain and possibly neurogenic inflammation. To shed light on these issues, we have developed a rodent model for studying pelvic organ reflexes, pelvic organ cross-talk, and associated striated sphincter activity that has allowed us to show that (1) colonic afferent sensitization occurs following the induction of acute cystitis and (2) urinary bladder sensitization occurs following the induction of acute colitis. Female Sprague-Dawley rats, 200–250 g in weight, were purchased from Hilltop Lab Animals, Inc (Scottsdale, PA) and housed in standard polypropylene cages with ad libitum access to food and water in the University of Pittsburgh's Central Animal Facility. All studies were approved by the University of Pittsburgh's Institutional Animal Care and Use Committee and were found to meet the standards for humane animal care and use as set by the Animal Welfare Act and the NIH Guide for the Care and Use of Laboratory Animals. In the first series of experiments, anesthetized female rats (n = 8) underwent placement of bladder cystometry catheters and intracolonic balloons. Abdominal electromyography (EMG) measurements were obtained during saline cystometry both before and after acute bladder irritation with protamine sulfate and KCl. In the second phase of experiments, a second set of anesthetized animals (n = 4) underwent placement of bladder cystometry catheters and underwent cystometric measurements before and after acute colonic irritation with trinitrobenzene sulfonic acid (TNBS). Female rats were first anesthetized with urethane (Sigma Chemical Co, St. Louis, MO) 1.2 g/kg subcutaneously; following a midline laparotomy, a transvesical, flared-tipped PE-50 catheter (Fisher Scientific, Hanover Park, IL) was inserted through the bladder dome via a small cystotomy and ligated for urinary bladder filling and pressure recording. The catheter tubing was externalized via the proximal aspect of the ventral abdominal incision and connected to a blood pressure transducer (World Precision Instruments, Sarasota, FL) and a syringe pump (Harvard Apparatus, Holliston, MA) via 3-way stopcocks. Normal saline was infused into the bladder at a rate of 0.1 mL/min for continuous open cystometry. A Transbridge transducer amplifier (World Precision Instruments) was used to amplify the signal from the pressure transducer, which was processed using a PowerLab 8s unit data acquisition system (ADInstruments, Mountain View, CA) connected to a Macintosh G3 computer (Apple, Cupertino, CA). Cystometry catheters were calibrated with water-filled tubing attached to the transducer, the meniscus at 0 and 100 cm, relative to the height of the bladder. Intracolonic balloons were fashioned from condom reservoir tips and PE-50 tubing. The balloon, which approximated the dimensions of a rat stool pellet, was inserted through the anus with its proximal tip positioned 4 cm from the anal verge and was attached to the tail with adhesive tape. Via 3-way stopcocks, the intracolonic balloon was connected to a pressure transducer for measurement of intracolonic pressure and a 1-mL saline-filled syringe for balloon distention. Intracolonic pressure signals were amplified and acquired as previously described. Balloons were calibrated and zeroed outside the animal. Balloon compliance was calculated as previously described.27Turler A. Moore B.A. Pezzone M.A. Overhaus M. Kalff J.C. Bauer A.J. Colonic postoperative inflammatory ileus in the rat.Ann Surg. 2002; 236: 56-66Crossref PubMed Scopus (109) Google Scholar Fine wire electrodes were fashioned from stainless steel polyurethane-coated wire (diameter, 50 μm; M.T. Giken Co, Ltd, Tokyo, Japan) and were percutaneously inserted into the external urethral sphincter (EUS), the external anal sphincter (EAS), and the lower abdominal wall musculature for EMG recording. The EMG signals were amplified using an IsoDAM8A biological amplifier (World Precision Instruments) and acquired by the PowerLab unit. The EMG signals were filtered (high frequency, 3 kHz; low frequency, 10 Hz) and acquired at a rate of 1000 samples per second. EMG frequencies were measured from the raw EMG signals using the PowerLab unit and expressed as spikes per second. The complete in vivo experimental preparation for measuring pelvic organ (urinary bladder and distal colon) and striated musculature (EUS, EAS, and abdominal wall) reflexes and reciprocal interactions during micturition under nonirritating and irritating conditions of either organ and/or sphincter stimulation in urethane-anesthetized rats is depicted in Figure1. Continuous bladder filling with normal saline was initiated following surgical preparation at a rate of 0.1 mL/min; however, to ensure measurement of stable baseline pelvic organ and striated musculature activity, no control measurements were obtained until after an acclimatization period of 45–60 minutes following the acute surgical manipulations and continuous open cystometry. Following the acclimatization period, control baseline urinary bladder contraction frequency, EUS EMG activity and frequency, abdominal EMG activity and frequency, and colonic pressure and contraction parameters were then measured for 30 minutes (control period). After completing the 30-minute control recordings, graded colorectal distentions (CRDs) were initiated while continuous bladder infusions (and micturition) continued. The intracolonic balloon was distended by graded infusions of 0.1 mL at 5-minute intervals for a total of 7 infusions (0.7 mL). Five minutes after the last infusion, the intracolonic balloon was returned to its predistention volume. Urinary bladder contraction frequency, EUS EMG activity and frequency, abdominal EMG activity and frequency, and colonic contractions were measured as previously described at each distention level. In a separate set of animals, the CRD paradigm was repeated during saline cystometry to assure stability of the response and to confirm that CRD itself did not induce colonic sensitivity. Acute urinary bladder irritation was performed using intravesical infusions of protamine sulfate and potassium chloride as previously described.28Fraser M.O. Chuang Y.C. Lavelle J.P. Yoshimura N. de Groat W.C. Chancellor M.B. A reliable, nondestructive animal model for interstitial cystitis intravesical low-dose protamine sulfate combined with physiological concentrations of potassium chloride.Urology. 2001; 57: 112Abstract Full Text Full Text PDF PubMed Google Scholar Briefly, protamine sulfate (Sigma Chemical Co) (10 mg/mL in normal saline) was infused intravesically in place of normal saline while continuous cystometric measurements were made. Thirty minutes later, bladder infusates were replaced with 300 mmol/L KCl at the same infusion rate. Graded CRDs and cystometric recordings were then made 30–40 minutes after initiating KCl infusion, when bladder irritation was both maximal and stable. Sensory thresholds to CRD were compared before and after acute bladder irritation. TNBS (5% aqueous solution; Sigma Chemical Co) was instilled intrarectally as previously described by Morris et al29Morris G.P. Beck M.S. Herridge M.S. Depew W.T. Szewczuk M.R. Wallace J.L. Hapten-induced model of chronic inflammation and ulceration in the rat colon.Gastroenterology. 1989; 96: 795-803Abstract Full Text PDF PubMed Scopus (1597) Google Scholar and modified by Appleyard and Wallace30Appleyard C.B. Wallace J.L. Reactivation of hapten-induced colitis and its prevention by anti-inflammatory drugs.Am Physiol Soc. 1995; 269: G119-G125PubMed Google Scholar to induce acute colonic irritation in animals undergoing saline cystometry under urethane anesthesia. Briefly, TNBS (50 mg/mL) dissolved in 50% ethanol (vol/vol) was administered via a transanal approach (total volume, 0.5 mL) using a PE-90 catheter with the tip placed approximately 4 cm proximal to the anal verge. Control animals received 0.5 mL of normal saline. Because recordings were made with rats lying in the supine position, any potential leakage of the TNBS from the colon, although not observed, would not come in contact with the perineum and hence the urethral sphincter. As an added precaution, Surgilube (E. Fougera & Co, Melville, NY) was applied to the perineum to minimize any potential contaminant irritation due to anal leakage. Following acute colonic irritation, urinary bladder contraction frequency and EUS EMG activity were then measured for 30–60 minutes. All data are expressed as mean ± SE and were analyzed using GraphPad Prism 3.0 statistical software (San Diego, CA). Parametric 2-way analysis of variance for repeated measures with Bonferroni's posttest was used to determine differences in CRD effects before and after acute bladder irritation. Urinary bladder intercontraction intervals (ICIs), which are indirectly related to bladder contraction frequencies, were compared in animals before and after the induction of acute cystitis or acute colitis. Paired t tests were used to identify statistically significant differences between and after each treatment. P < .05 was considered significant in all instances. A typical tracing illustrating rhythmic bladder activity, EUS, EAS, and abdominal wall EMG activity during the continuous infusion of saline into the bladder (saline cystometrogram) is shown in Figure 2 (11-minute excerpt). During these control conditions, the interval between urinary bladder contractions, the ICI, was 5.9 ± 0.4 minutes (n = 8) and was typical for nonirritated bladder contractions during saline cystometry at a flow rate of 0.1 mL/min in female Sprague-Dawley rats of this age. Figure 3 represents an expanded, 15-second excerpt of the tracing in Figure 2. Note the simultaneous, phasic firing or bursting (high-frequency alternating period of EMG activity vs silence) of both the EUS and the EAS and the tonic (sustained) firing of the abdominal wall during bladder emptying. During micturition, EUS firing very intimately and precisely entrained the EAS as one might expect to see in a direct neural circuit. This coordinated bursting of sphincters occurred at an average frequency of 4.3 ± 0.6 Hz. Mutually independent EAS and EUS activities were also noted and included both tonic and phasic firing of the EAS independent of micturition and tonic postmicturition EUS activity lasting 1–3 minutes following micturition-associated EUS phasic firing (Figure 4) (14.5-minute excerpt).Figure 4In vivo physiologic recording showing an inhibitory bladder-to-bowel neural reflex. Colonic activity is inhibited (arrows) during micturition and remains inhibited until the tonic phase of the postmicturition EUS activity subsides. Mutually independent EAS and EUS activity are also noted and include both tonic and phasic firing of the EAS independent of micturition and tonic, postmicturition EUS activity lasting 1–3 minutes following micturition-associated EUS phasic firing (14.5-minute excerpt).View Large Image Figure ViewerDownload (PPT) The measurement of distal colonic motility during saline cystometry is also shown in the tracing in Figure4. Note the regularly paced, spontaneous colonic contractions as recorded by the intracolonic balloon. These colonic contractions occurred every 30–40 seconds when present. Interestingly, it was consistently observed that colonic activity was inhibited (Figure 4, arrows) during micturition and remained inhibited until the tonic phase of the postmicturition EUS activity subsided, suggesting a reciprocal inhibitory neural reflex (bladder-to-bowel and EUS-to-bowel reflex, respectively). Analogously, Figure 5 shows that graded CRDs lead to inhibition of micturition and EUS activity, suggesting a reciprocal inhibitory bowel-to-bladder and bowel-to-EUS reflex. The appearance of non-micturition-associated abdominal EMG contractions, a consequence of noxious CRD, occurred after the inhibition of micturition, suggesting that the threshold for pelvic organ cross-inhibition is lower than that for the visceromotor response to CRD. Rhythmic micturition-associated reflexes promptly returned following cessation of CRD. As expected, CRD inhibited anal sphincter activity. Cessation of CRD led to suppression of micturition-associated abdominal contractions and more prominent anal sphincter activity as compared with predistention levels. Anal distention was not associated with an increase in intravesicular pressure, but a moderate increase in EUS activity was noted (not shown) and is consistent with its role to maintain urinary continence during defecation. The urinary bladder ICI, a measure of micturition cycle length and therefore inversely related to micturition frequency, was measured during saline cystometry and following protamine (10 mg/mL) and KCl (300 mmol/L) intravesical infusions. Protamine itself decreased the ICI by 23% compared with saline (P < .05), while the combination of protamine and KCl reduced the ICI by 74% (P < .0001) (Figure 6). The shortening of the ICI (increasing micturition frequency) reflects lower urinary tract afferent sensitization or irritation. An example of recorded intravesical and intracolonic pressures and abdominal EMG activity during CRD in an animal before and after the induction of acute cystitis is shown in Figure 7. Graded CRDs to 60 cm H2O produced no notable changes in abdominal wall EMG activity before the induction of acute cystitis (Figure 7A). In Figure 7B, note the decreases in the bladder ICI following intravesical irritation with protamine sulfate and KCl. Following acute cystitis, increases in basal and micturition-associated abdominal wall EMG activity were noted at CRD pressures much lower than 40 cm H2O, indicating bowel hypersensitivity as a result of cross-sensitization in this model. In Figure 8, normalized abdominal wall baseline (non-micturition-associated) EMG recordings are represented for each CRD volume both before and after bladder irritation. Statistically significant differences were noted at the 0.4- and 0.5-mL CRD levels (P < .001). At the 0.7-mL level of CRD, the visceromotor response was equivalent in both groups.Figure 8The effects of acute KCl cystitis on basal (non-micturition-associated) abdominal EMG activity in response to sequential intracolonic balloon distentions. *P < .001 (2-way repeated-measures analysis of variance; Bonferroni's posttest analysis).View Large Image Figure ViewerDownload (PPT) A tracing illustrating lower urinary tract activity during continuous cystometry before and after colonic irritation with intrarectal TNBS is shown in Figure 9. Following acute colonic irritation and consistent with urinary bladder sensitization, urinary bladder ICIs decreased 66% ± 3% (P < .05) (Figure 10). Typically, this decrease in the ICI or increase in bladder contraction frequency was noted after an immediate period of bladder inhibition lasting 2 micturition cycle lengths (ie, as early as 7 minutes).Figure 10Bladder ICIs before and after intracolonic TNBS administration (n = 4). *P < .05.View Large Image Figure ViewerDownload (PPT) We have shown compelling evidence of neural cross-talk and bidirectional cross-sensitization in the pelvis using a novel experimental model. The ability to measure concurrently lower urinary tract and distal colonic sensory function and striated sphincter activity in response to cross-organ, nonirritative and irritative stimulation substantiates the importance of this model in studying pelvic pain and the overlap of CPP disorders such as IBS and IC. As shown in Figure 4, Figure 5, pelvic organ, nonirritative stimulation or spontaneous physiologic activity led to apparent cross-inhibition of motor function in the nonirritated organ. Specifically, spontaneous colonic motility was inhibited during micturition, while non-noxious CRD led to inhibition of m
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