Rectal afferent function in patients with inflammatory and functional intestinal disorders

P 66 (1996)151-161 @ 1996International Associationfor the Studyof Pain.All rights reserved0304-3959/96/$15.00

PAIN3062

Rectal afferent function in patients with inflammatory and functional intestinal disorders Charles N. Bernsteina,Negar Niazib, Marie Robertd, Howard Mertzc, Anatoly Kodnerc, Julie Munakatab, Bruce Naliboffb’cand Emeran A. Mayer*’b’c aDepartment of Medicine, University of Manitoba, Winnipeg, (Canaak), bCURE Digestive Diseases Research Center/Neuroenteric Biology Group, ‘Department of Medicine, UCLA, Las Angeles, CA, (USA), ~Department of Pathology, UCLA, J% Angeles, CA, (USA) and VA Medical Center, West LQs Angeles, Los Angeles, CA W073, (USA)

(Received13Decemtnx1994,revisionreceived8 December1995,accepted4 January 1996)

Chronicsymptomsof abdominalpain and discomfortare reported by patientswith inflammatorybowel disease(IBD) and functionaldisordersof the gut, such as Irritable BowelSyndrome(IBS).It has recentlybeen suggested that transient inflammatory mucosal events may result in long-lasting sensitization of visceral afferent pathways.To determine the effect of recurring intestinal tissueirritation on lumbosacralafferent pathways, and to identifya plausiblemechanismthat could account for the overlapin symptomatologybetweenIBD and IBS,we compared rectal afferent mechanismsin patients with Crohn’s disease (inflammationlimited to the ileum) with those observedin patients with diarrhea-predominantIBS. Continuous volume ramp and phasic pressure step distension of a rectal balloon were performed in 9 healthy male control subjects, 12 male patients with isolated ileal Crohn’s diseaseand 9 male patients with diarrhea-predominantIBS using an electronicvisceralstimulationdevice.The response of rectal afferents to distensionwas evaluated by measuring thresholds for the perception of physiological (stool) and aversive(discomfort)sensations,viscerosomaticreferral patterns, skin conductanceresponses,receptive relaxation,and rectoanalreflexresponses.In responseto slowramp distension,thresholdsfor aversivesensationswere significantlyhigherin Crohn’sdiseasepatients, but similarbetweenthe two other groups. In responseto rapid phasic distension,IBS patients reported discomfortat lowerdistensionpressures,whileall other thresholdswere similarbetween groups. Skin conductance responsesto aversivedistensionwere greatly reduced in Crohn’s diseasepatients whileIBSpatientshad greater responseswhen comparedto normals.Changesin viscerosomaticreferral patterns and receptiverelaxation rate were similar in Crohn’s diseaseand IBS patients. These tindingsdemonstrate that chronic ileal inflammationis associatedwith increasedthresholdsfor discomfortand greatly diminishedsystemicautonomic reflex responses. In contrast, IBS patients show lowered thresholds for discomfort associated with increased autonomicresponses.The findingsin Crohn’s patients may result from descendingbulbospinalinhibition of sacral dorsal horn neurons in response to chronic intestinal tissue irritation. Slutlmary

Key words: Crohn’s disease;Irritable BowelSyndrome;Visceralafferents;Spinal cord; Hyperalgesia

Introduction In the current study,we evaluatedrectalafferentfunction in two patient groups with chronic symptomsof abdominal pain and discomfort: patients with the irritable bowel syndrome (IBS) and patients with inEmeran A. Mayer, VA Medical Center West Los Angeles,Bldg. 115/CURE,Los Angeles, CA 90073,USA. Tel./Fax: (310)3129276. Abbreviations: EAS, external anal sphincter;IAS, internal anal sphincter; IBS, Irritable Bowel Syndrome; IMG, inferior mesetttericganglion.

* Corresponding author:

PII

S0304-3959(96P3062-X

flammatoryboweldisease(Crohn’sdiseaseof the small bowel). In patients with IBS, chronic visceral hyperalgesia (LaMotte 1992)has been suggested as a mechanism responsible for characteristic symptoms of chronic abdominalpain and discomfortwithout detectable organic cause (Mayer and Raybould 1990; Mayer and Gebhart 1993).Even though differencesin true visceral pain thresholds between normal subjects and IBS patients have not been reported, rectosigmoid visceral hyperalgesiais suggestedby patients’reports of chronic abdominalpain/discomfort,tendernessover the sigmoid colon, and excessivediscomfortduring traction on the

152

sigmoidduring sigmoidoscopicexaminations.We have recently shown that nearly all IBS patients show evidence for altered perception of phasic rectal balloon distension in the form of lowered discomfort thresholds, increased intensity of perception or altered viscerosomatic referral (Mertz et al. 1995).The mechanism(s)

underlyingalteredvisceralperceptionin IBSis currently not known, but may involve peripheral, spinal or supraspinalsites (Mayer and Gebhart 1994). In contrast to IBS, chronic abdominal pain is not a frequent symptom of patients with uncomplicated Crohn’sdisease,a syndromecharacterizedby recurring transmural inflammationof the gut, affectingprimarily the smalland large intestine.Similarly,chronicmucosal inflammationof the stomach(chronicgastritis)or colon (ulcerative colitis) is generally not associated with chronic pain. Since acute inflammation of esophagus (Garrison et al. 1992),colon (Ness and Gebhart 1990; Blumberget al. 1983)and urinary bladder (Haebler et al. 1990)in animal models leads to functionalchanges in primary and secondaryafferent neurons resultingin acute visceral hyperalgesia,one might expect that inflammation of the small intestine in Crohn’s disease shouldalso result in hyperalgesiaof splanchnicafferent pathwaysprojectingto the thoracolumbar spinal cord. However, counter-regulatorymechanismsactivated by persistent tissue irritation may explain the absence of hyperalgesiain chronic inflammatoryconditions of the gut. Counter-regulatory mechanisms may include neuroplastic changes in afferent pathways (Dubner 1992),or the activation of tonic descendinginhibitory pathways (Duggan and Morton 1986).Increased tonic and/or phasic descending inhibitory pathways (Willis 1988;Le Bars et al. 1979)maybe responsiblefor the increased somatic pain thresholds previouslyreported in patientswith disordersassociatedwith chronicpain syndromes (I-e Bars and Dickenson 1979), or chronic visceralpain such as Crohn’sdisease(Cook et al. 1987). Alterations in counter-regulatorymechanism may explain atypical presentationsof patients with functional and inflammatorybowel disorders. For example some patients with inflammatorybowel diseasecomplain of abdominalpain andlor discomfortwhen their diseaseis known to be in remission by endoscopic and radiologicalcriteria (Isgar et al. 1983).Alternatively, some previously asymptomatic individuals develop symptoms indistinguishable from IBS following an acutegastroentericinfectionwith inflammatorychanges of the mucosa (Chaudhary and Truelove 1962). While conscious perception of physiologicalrectal sensations(fullness,urgency)is thought to be mediated primarilyby sacralafferents(Krier 1989),splanchnicafferent projectionsfrom the rectum to the lumbar cord are not essentialfor perception of normal rectal sensations (Ray and Neil 1947).However, these splanchnic pathways play an important role in the perception of

painfulstimuli(Binghamet al. 1950),are likelyto play a role in the mediation of certain reflex responses (Janig et al. 1993),and may be involved in mediation of discomfortin responseto rectal balloon distensionin IBS patients (Lemboet al. 1994).By studyingthe function of differentrectal and anal afferent mechanismsin normal controls, Crohn’s diseasepatients with ileal involvementonlyand diarrhea-predominantIBS patients, we wanted to test the following two divergent hypotheses:(1) chronic ileal tissue irritation in patients with Crohn’sdiseaseresultsin chronic hyperexcitability of dorsalhorn neuronsof the thoracolumbarspinalcord whichis associatedwith recruitmentof subthresholdafferent inputs (Woolf and King 1989) from the rectosigmoidcolon. Such central hyperexcitabilitywould lead to altered perception of rectal distension and abnormal viscerosomaticreferral patterns, similar to those seen in IBS patients. In addition, one may expect changesin reflexrelaxationof the rectal wall and in internal anal sphincter (IAS) function, and increased autonomicstimulation.(2) Chronic visceralpain stimulated by inflammation in one area of the bowel (the ileum) results in the activation of diffuse noxious inhibitory controls (DNIC; (Willis 1988;Le Bars et al. 1979)).Diffuse descending inhibition elicited by continuous afferent input could have two different results: by decreasingthe excitabilityof affected dorsal horn neurons, it may result in increased sensory perception thresholdsat a distantintestinalsite(suchas the rectum) or in somatic structures. Alternatively,it may depress backgroundactivityof the affecteddorsal horn neurons which in turn could increase the signal-to-noiseratio when theseneurons are activated from another visceral organ. This might result in an increase in intensity and/or a loweringof the thresholdfor physiologicalsensationsand discomfort.By comparing responsesin IBS patients and Crohn’s patients, we also aimed at elucidating differences in the pathophysiology of visceralpain in these two syndromes. Metbods To eliminatepossibleinfluenceson sensoryperceptionbyvariations in femalesteroid hormonelevels(Heitkemperand Jarrett 1992),we chose to perform studies in male subjects only. Normals Ninehealthymalesubjectsbetweenthe agesof 28and 52(meanage 40 years) were recruited by advertisement.None of the subjectshad any evidence(by history or physical examination)for an acute or chronicillness.In particular, there was no evidencefor a chronicpain syndrome,or for abdominalsymptomseither bybowelsymptomquestionnaire or by personal history. Crohn’spatient.v

Twelvemalepatients with knownisolated ileal Crohn’sdiseasetx.tweenthe agesof 22and 56(meanage 37)whowerewillingto participate in the protocol were recruited from the UCLA Inflamrnatory

153 BowelDiseasecenter. The presenceof ilealdiseasewasdeterminedby colonoscapywith ileal incubationor by smallbowelradiographin all patients, and all had someform of ilealexaminationwithin 3 months of studyparticipation.Allpatientshad beenfollowedat the UCLAInnantrnatoryBowelDisease(IBD)Centerfor a minimumof 1year, and they had colonoscopieswith biopsiesindicatingabsenceof colorectal &ease within 1month of the study. None of the patients complained of abdominalpain. Nine patients had mild symptomsand did not require anti-irttlarnmatoryor itmmmosuppressivetherapy, while 3 patientshad activediseaserequiritrglowdosesof oral prednisone(15-30 mglday).The clinicalcharacteristicsare sununarid in Table L

moduIatedprimarily by sympatheticactivity (Fowles 1986),during rectrddistension.Electrodermaiactivitywas measuredby a Beckman SkinConductanceCoupler(type 9844).Prior to electrodeplacement, the surfaceof the skinwascleanedwith an isopropylalcoholpreparatory pad and subsequentlyallowedto dry. The electrodes(8 MMdiameter, silver-silverchloride) were filled with electrode gel (TECA, P1easantville,NY) and attached by adhesiveelectrode collars to the distal phalangesof the secondand third fingersof the non-dominant hand. A 30 mitt stabilizationtime permitted a controlledinterface of the electrodegel and skin surface (Fowleset al. 1981). Volume-displacementdevice

IBSpatients

were willingto participate in the protocol were recruited from the UCLA Carter for Functional BowelDisordersand AbdominalPain. A diagnosisof IBS was made using the exclusionof organic disease, the so-calledROME criteria (Drossmanet al. 1990)and the diagnosis of 1of 4 gaatroenterologistsexperiencedin the evaluationof functional twwelpatients. A diagnosisof diarrhea-predominantIBSwas made usingthe followingcriteria from the modifiedTalleyBowelSymptom Questionnaire (Tafley et af. 1989):patients had to refer to their predominantbowelhabit as diarrhea, report regufarurgencypreceded by abdominalcramps, report norrnaf,soft or liquid stools and score negativeon questionsfor constipationand hard stools. IBS patients withdiarrhea onlywerechosenas a control group,sincethe predotninant symptoms(i.e. diarrhea, crarnpyabdominalpain) is identicalto that of Crohn’sdiseasepatients. Symptomseventy of the predominantsymptom(for both Crohn’s and IBS patients) at the time of the initial contact with the Center physicianwasestimatedusingthe patient’sresponseon a singfe 10 CM visual anafogueacafe.The scaleasked for a rating of their current GI symptomand was anchoredon one end by ‘extremelysevere’and on the otherby ‘bearable’.The midpointwasanchoredby ‘moderatelysevere’.Ratingsare in cm from the ‘bearable’end of the scafe.Average frequencyof bowel movementsand presence of validated symptom criteria (Manninget af. 1978)in rdl patients were assessedusing the modifiedTalleybowelsymptomquestionnaire(Talleyet al. 1989).Severity of psychologicalsymptoms were assessed using the SCL-90 psychometricinventory(Derogatis 1983). Patientswereconsideredhypersensitive(or hyposensitive)for stool (or discomfort)if their respectivepressure threshold was below (or above)the 95°Acotildence interval of the normal control group. The studywas approvedby the West Los AngelesVeteransAdministration Research and Hunran Studies Committees,and informed consentwas obtained from each subject.

A computer-operated volume-displacement device (Syrtectics VisceralStimulator,SYNECTICS,Stockholm)was used to inflate a ballooneither continuouslyat a constant volumerate of 40 MI(ramp distension),or rapidly to constant pressure plateaus (phasic distension).Thedistensiondevice,whichrecordspressures(monitoredat the distensiondevice)and volumessimuftrmeously(samplingrate I see-’) wasconnestedto a subject-operatedmarker devia whichlogsthe sensations of stool or discomfortonto the data file as bafloon inflation occurs(Plourdeet al. 1993).Whena subjecttriggeredthe marker for discomfortduring phasic and ramp distension,the distensiondevice instantaneouslydeflated.There was a fixedpressure-limitwhichalso triggeredballoondeflationfor pressuresabove 70 mmHgor volumes above650cc. A latexballoonwasattachedto a silastictube (ED = 18Fr) and tied at both proximaland distal ends (MAK-LA,Los Angeles,CA). The distancebetweenthe twoattachmentsiteswas 11cm.The balloonwas inflatedrepeatedlyprior to use to rule out any leak and to measureits intrinsiccompliance.In preliminarystudies it was found that during the initial 3 balfoon irdlations, the maximally reached balloon pressures decreased by 10%. Following this initial decrease, the vohune-preasurerelationshipof the balloonremainedconstant for up to 10 subsequentinflations. During inflation, the balloon pressure rapidly increasedto 10 rnmHg,and remained constant at this level with increasingvolumes.To determine sensory thresholds to ramp distensions,brdloonpressuresat each volumewereautomaticallysubtracted from rectal pressuresby the barostat software.The balloons were tested again followingcompletionof each experimentto ensure therewasno leakor changein compliant with repeatedinflation.The lubricated balloon was inserted into the rectum, so that the distal attachment site was 4 cm from the anal verge. The tube was then securedin its proper position with tape. The responsecharacteristicsof the distensiondevicein vivoand in vitro have previouslybeen described(Lemboet-al. 1995;Mertz et al. 1995).

AM1 canal nranometry

Str4dy &sign

Resting and stirnufated pressures within the anal canal were monitoredwith a mrdtihunenwater-periirsedcatheter assemblywith sixradirdlydistributedsideholes,spaced0.5cm apart. Appropriatelocation of the catheter was verifiedbefore each experimentby a pressure increase observed during a voluntary squeeze and a pressure decreasein responseto intrarectal balloon inflation.The pressureresponseof the anal sphincterto stimulationof afferentswithinthe anal canal was determinedby pulling a plastic catheter through the anal canal (1 CMper 30 sez), while recording from a second, stationary water-perfusedcatheter. The response was expressedas stimulated pressureminusresting pressure. Stimulationof anal rdTerentsprojecting to the sacral spinal cord by shearingforces has previouslybeen shownto be a stimulusfor Iumbosacrrdreflexesregulatingboth external (Bishop1959;Bishopet rd. 1956)and internal (Bartel et al. 1986) anal sphincters.

For all studies,subjectswereplaced in a lateral decubitusposition on a padded table. The examinerwas alwayspresent, but did not interact with the subjectsafter the initiaf explanationof the respective task. Patients were not instructed about the nature of the distension protocols,i.e.continuousramp distensionvs. phaaicdistension.It was emphasizedto the subjectsthat theyhad fidl control over the protocol by being able to deflate the bafloon ins~taneoosly at any time of significantdiscomfort. Subjects had no visual or auditory cues to anticipatethe type or the time course of distensions.All experiments were performedafter a 12h fast and followingthe application of 2 Fleets’enemas. Subjectswere studied on two differentdays. on day 1, perception thresholdsand reflexresponsesweredeterminedduringthe ascending phasicdistensionprotocol and during slow ramp distension.On day 2, discomfortthresholdswere determinedagain using an interactive trackingprotocol.In addition,skin conductanceresponses duringthe tracking period were recorded.

Nine mafepatients betweenthe agesof24and 38(meanage29)who

Skin conductancemeasurements

Nociceptive visceral stimulation is associated with significant autonomicresponses(J~nigand Habler 1995).If alterations in rectal afferentmechanismsdifferbetweenthe two patient groups,one would afsoexpectdifferentsympatheticresponsesto an aversiverectal stimulus. In order to determine possible differences between the study groups we monitored skin conductance, a physiologicalparameter

Day 1

Perceptionthresholdsfor stool and discomfortwereestimatedduring semi-randomlyascending pressure pukes (10-70 rnmHg in 5 rnrnHgincrements)(Plourdeet al. 1993)of 30 sec duration. Pressure pufseswere separated by 60 wc intervafsat the resting pressure of 2 rnmHg.Each pressure step was onlygivenonce. In addition, percep-

154 tion thresholdsfor stool and discomfortwere estimated during slow ~P distension oftherectum.Thedifferentdistensionprotocolswere separatedby a 10min restingperiod and the sequenceof the 2 distensionprotocolswasgivenin randomorder. Eachgroupreceiveda comparable number of stimulation sequences.In response to the phasic rectal distensionprotocol, the followingparameters were monitored: (a) perceptionthresholdsfor stool (innocuoussensation)and discomfort (aversivesensation);(b) viscerosornaticreferral; and (c) the rate of receptiverelaxation,expressedas the volumeincreaseobservedduring the isobaricphase of the pressurestep (for details, see Evaluation of outcomeparameters, below).In responseto ramp distension,only perceptionthresholdswere determined. Day 2

Duringthe sensorythresholdtrackingparadigm,the computerpromptedthe subjectto respondat constant intervals.The responsetask was to choose betweenthe followingratings of the perceivedsensation: no sensation;moderatesensation,discomfort,pain; the prompts ap~ at ~h of the alternatingpressure steps and baseline. A seriesof ascending15sec square wavepressuresteps (incrementsof 5 rmnHg)weredeliveredfroma 30seestatic baseline(5rnmHg)untilthe subject triggered discomfort on a subject marker device. More specifically,if the subjectindicatedan intensityof sensationbelowthe tracked intensity,the next pressure step incremented5 mmHgabove the precedingone. Conversely,if the subjecttriggeredthe tracked intensity of sensation(i.e. discomfort),the followingpressurestep was randomizedto eitherremainthe sameas the prexx.ding oneor to deaement 5 mmHg. In the event of a pain response,in all instances the fotlowingpressurestimuluswas 5 rnrnHgleasthan the previousstimulus. This tracking protocol rapidly rises to discomfortthreshold and maximim the numberof stimrdigivenat about discomfortthreshold. The randomelementwas placedin the trackingparadigmto mask the relationship between ratings and subsequent stimulus change and thereforedecreasepotentialscalingbias whichmightoccurwitha simple tracking protocol (Grady et al. 1988). Evaluation of outcome parameters Perception threshokiv

Thresholdswere expressedin referenceto intrarectal pressure and to rectal wall tension. As the precise geometryof the rectum during balloondistensionis not known,we estimated rectal watl tension by assumingeither a sphereor a cylinder.In each case, wall tensionwas calculatedusingL.aPlace’sLaw,fromthe balloonvolumeand pressure at eachstooland discomfortthresholdduringramp distension(Lembo et al. 1995;Mertz et al. 1995).Since similar threshold changeswere observedfor both types of tension estimates, wall tension estimates basedon a cylinderwereusedin this study.Pain thresholdor pain tolerancewerenot evatuatedin the current study.Wechosethe threshold for discomfortas the upperlimitof the responseparameterand the patient was givencontrol over the distensionpressureto preventfurther distensiononcediscomfortwasexperienced.Thisstudydesignallowed us to minimizethe emotionaland autonomicresponsesassociatedwith repeatedtransitionsof visceralpain thresholdsand increasedthe subjects’acceptance of the test. Wehavepreviouslyshownthat thresholds determinedin normal control subjectsusingramp and phasic distensionare hightyreproducibleover a period of severalmonths(Plourde et al. 1993). During both ramp and ascending phasic distension protocols, thresholdsweretaken as the first pressureat whicha subjectindicated the sensation of stool or discomfort. During the tracking protocol, perceptionthresholdsfor discomfortwere determinedfrom a 10tin sensory threshold tracking. The last six stimulus pressures during whichthe subjectindicatedthe sensationof discomfortwereaveraged to determinethe discomfortthreshold. Viscerosomoticreferral

During each phasic rectal distension,patients were asked to draw the area overwhichtheyperceivedthe respectivesensationson a body ~P (plourde et al. 1993;Ness et al. 1990). Autonomicarousal In responseto rapid phasic distensionof the rcdurn, the level of sympatheticactivationwasestimatedusingskinconductancemeasure-

ment (Fowleset al. 1981).Electroderrnalresponsesduring periods of discomfort threshold tracking were quantified by determining the number of fluctuations (peaks) in skin conductance (Reiman et al. 1989). Receptive relaxation

Eventhoughthe precisepathwayswhichmediatethe active relaxation of the rectal wallin responseto distensionare not known,it may be assumedthat analogousto the stomach,both intrinsicand extrinsic reflexesare involved(Bishop1959;Bishopet al. 1956;Krier 1989).The volumeincreaw observedduring the isobaric phase of the pressure stepwastaken as a measurefor the active(receptive)relaxationof the rectal wall. This relaxation was quantified as a rate by dividingthe observedvolumeincrease(betwem 10and 30secof the pressurestep) by 20 w as previouslydescribed (Lembo et al. 1995;Mertz et al. 1995).

Data throughout the manuscript are expressedas mean values + S.E.M.The t-test statistic was used to evaluate group differencesfor continuousvariables.All statistical endpoints were determinedprior to conductingstatisticalanalysis.Significantdifferencesare expressed at the P < 0.05 level. For non-significanttests, actual P values are reported. No correction was employedfor multiplecomparisons.

Results Clinical characteristics of patient population

Age, number of bowel movementsper week, subjective symptomseverityand number of Manning criteria for Crohn’sand IBS patients are summarizedin Table I. Frequent and looser bowel movements associated with abdominalpain, and reliefof abdominalpain with bowelmovementswas reported 3 timesmore commonly by IBS patients when compared to Crohn’spatients. A sensationof incompleteevacuationwas reported by 8/10 of the IBSpatientsbut by only 1Crohn’spatient. Visible abdominaldistensionand the sensationof bloatingwere reportedby 3/10IBSpatientsand 5/12Crohn’spatients. Mean tscoresof any symptomdimensionon the SCL-90 werelower than 63 (belowsignificancelevel),and there was no significantdifferencein any dimensionbetween the two patient groups. Perception of rectal distension Ramp distension (Fig. 1A)

When expressed as intrarectal pressure, mean thresholdsfor the sensation of stool were not different betweenthe three groups. In contrast, mean discomfort thresholdsin Crohn’s diseasepatients (44 + 5 mmHg) werehigherwhencomparedto normals(30 + 2 mmHg; P < 0.05).Therewasno differencein sensorythresholds betweenCrohn’sdiseasepatientswith activediseaseand those in remission. There was no difference between normals and IBS patients. Mean volumethresholdsfor the sensationof stool in Crohn’sdiseasepatients (193 + 19ml; P < 0.05) were nearlytwiceas high as those in normals(77 + 26 ml) or in IBS patients(111 + 18ml; P < 0.05).Mean volume

155

TABLE I CLINICAL CHARACTERISTICS

CD IBS

Age (years)

No. of positive Manning criteria

No. of bowel movements/week

Symptomseverity

37 (22-56) 29 (24-38)

2.9 (O-6) 4.2 (3-6)

15 (5-26) 15 (9-26)

7 (3-9) 4 (l-7)

Data presented as means (range).

thresholdsfor discomfortin Crohn’spatients (370 * 35 ml)werehigherthan in IBSpatients (182 * 18ml; P < 0.05) but similar to normals (300 + 30 ml; P = 0.16). When expressed as wall tension, the threshold for

A

so.

p
50. 40.

Ascendingphasic distension (Fig. IB)

2 ~. E E m. 10.

0

Normal

CD

16s

STOOL

B

stool was similar in Crohn’s patients (78 + 10 mrnHg x cm) when compared to normals (74 + 10 mmHg x cm: P = 0.79) or for IBS patients (74 + 16 mmHg x cm; P = 0.83). In contrast, the threshold for discomfort was higher in Crohn’s patients (289 + 44 mmHg x cm), when compared to IBS patients (139 + 19mmHg x cm; P < 0.05),but not statistically different from normals (180 + 12 mmHg x em; P = 0.05). There was no difference in thresholds between IBS patients and normal subjeets.

NOmmt

CD

IBS.

DISCOMFORT

m. 50.

Mean pressure thresholds for stool were similar betweenall three groups. For the sensation of discomfort, mean pressure thresholds in Crohn’s disease patients (48 + 5 mmHg) were similar to thresholds in normals (44 * 4 mmHg; P = 0.56). In contrast, IBS patients had lower mean thresholds (22 + 2 mmHg) than either of the other two groups (P c 0.05). Three out of 12 Crohn’sdiseasepatients and all of the 9 IBS patientswere found to be hypersensitive.There was no difference in sensory thresholds between Crohn’s patientswith activedisease(i.e. those requiringmedications) and those in clinicalremission.

40.

Trackingprotocol The mean pressure thresholds for discomfort in

%’ 30. E E

Crohn’s disease patients (33 + 4 mmHg) were not statisticallydifferent from values obtained in IBS patients(27 + 6 mmHg;P = 0.05),or from thoseobtained in normal control subjects(37 + 4 mrnHg; P = 0.50).

al. ,0. 0 Normal

CD

IBS

Nomnl

CD

IBS

Viscerosomatic referral STOOL

DISCOMFORT

Fig. 1. Perceptionthresholdsfor stool and discomfortduring rectal distension.Shownare mean vatues + S.E.M.for intrarectal pressures for normal subjeots,Crohn’sdiseasepatients (CD) and patients with irritable bowel syndrome (IBS). (A) Perception thresholds during ramp distension. Discomfort thresholdin Crohrr’spatients was higher whencomparedto normals(P e 0.05)or IBSpatients.Therewereno significantdifference for the sensationof stool betweenany of the 3 groups.(B) Perceptionthresholdsduring phaaic distension.Discomfort thresholdsin IBSpatients were lowerwhencomparedto nonrmls (P < 0.05) or Crobn’s disease patients. There was no difference betweenCrohrr’spatients and norrnats.

Subjects from all groups referred sensations in response to rectal distension up to 10 mmHg to the perianal area (S3 dermatome). While only one normal subjectreported the experienceof discomfortto an abdominalsite, 60%of the Crohn’s diseasepatients (6/10) and 56’%0 of the IBS patients (5/9) reported abdominal referral patterns (Table II). The most common referral sites in Crohn’s disease patients were the suprapubic area and the right lower quadrant. In IBS patients, all atypicalreferralswere to the suprapubic area. Of the 6 Crohn’s disease patients with abnormal referral areas, only 2 werehypersensitivefor discomfortduring phasic

156

8T—

TABLE II REFERRAL AREA OF DISCOMFORT EXPERIENCED DURING RECTAL DISTENSION

7

~ E a %5 ~

6 -

:4 $ <3 8 c “$2

Referral area

Normal

CD’

IBS

Perineum Suprapubic Left lower quadrant Right lower quadrant

9/9 1/9 019

9/10 4/10 1/10

9/9 5J9 0/9

0/9 1/9

3/10 6/10

0/9 519

Anyaberrantreferral

T

p
1

‘Of patientswithCrohn’sdisease,1 of 12 patients did not plot their referralpattern and 1of 12did not sensediscomfort up to 70 ruxnHginflation pressure.

0 — IBS

Normal

Crohn’s

Fig. 2. Effect of rectal distensionon skin conductance.Averageskin conductance(in p-sakahnin)recordedduringa 10rnintrackingp-miod (at discomfortlevel)in normal subjects(open bar), IBSpatients (hatchedbar) and in Crohn’sdiseasepatients (solidbar). Shownare mean values + S.E.M.

geneous,with 3 out of 9 patients showinga normal skin conductance response, and 6 subjects showing an increasedresponse. Receptive relaxation

distension,whilethe remaining4 had normal discomfort thresholds. Autonomic arousal

Fig. 2 showsaveragedskin conductanceresponses(in peaksper rein) obtainedduring the 10tin trackingprotocol.The responseobservedin Crohn’sdiseasepatients (0.2 + ().1) WaS lower when compared to normals (1.4 * 0.3; P e 0.05), but not statistically different from IBS patients (4.6 + 2.1; P = 0.06). While all Crohn’s disease patients showed decreased autonomic responses, the response in IBS patients was hetero400,

, 0 ● A

Normal Crohn’s IBS

I

.

.

50 I

OL

I

/

Fig. 3 showsthe rate of receptiverelaxation (isobaric volumeexpansion)at increasingdistensionpressures.In all three groups, the rectal wall relaxed progressively faster at greater distension pressures. In normal subjects, rates increased 7-fold from 45 + 7 mlhnin at 15 mmHg to 314 + 49 ndhnin at 40 mmHg. The correspondingvalues in the Crohn’s diseasepatients were 22 + 1 and 155 + 17 mmHg/min.When compared to normals, relaxation rates in Crohn’s disease patients were lower at most distensionpressures, but similar to rates observedin IBS patients. Anal sphincterfwction

As shown in Table 111,resting pressures in the anal canal were higher in Crohn’s disease patients (91 + 8 mmHg; P < 0.05) and in IBS patients (130 + 12 mmHg; P c 0.05)when compared to normals (64 + 9 mmHg). There was no difference between the three groups in the threshold for the rectoanal inhibitory reflex.The increasein anal canal pressurein responseto stimulationof afferents in the anal canal was severalfoldhigherin Crohn’sdiseasepatients (86 + 20mmHg; P < 0.05) and in IBS patients (70 + 21 mmHg; P < 0.05) when compared to normals (19 + 10 mmHg). Maximalsqueezepressureswere higherin both Crohn’s diseasepatients(278 + 22 mrnHg;P < 0.05)and in IBS patients (289 + 18 mmHg; P < 0.05) when compared to normals (124 * 11 mrnHg).

Eisid4! 10

15

20

25

30

35

40

J

Pressure(mmHg)

Fig. 3. Receptiverelaxation. Shown are mean values + S.E.M. for receptiverelaxationrates (rnlhnin)for the 3 groups. *Indicatedifference betweennormals and Crohn’spatients (P < 0.05).For clarity, error bars are not shown for IBS patients. Relaxation rates were determinedas describedin Methods.

Discussion We have shown that the majority of male patients with chronicintermittentinflammationof the ileumbut

157

TABLE III ANAL CANAL PRESSURES

Resting pressure Maximalsqueezepressure A pressurechange post pullthrough Pressurefor stimulation of anorectal inhibitory reflex

Normal

CD

64*9 124+ 11 19 * 10 19 * 2

91 + 278 + 86 * 18 +

IBS 8** 22* 20* 2

130* 12* 289 & 18 70 * 21 16 + 2

The data are expressedin rnmHgas means A S.E.M. ●P < 0.05.

**p= ())6.

without significant spontaneous pain do not exhibit hypersensitivityto phasic rectal balloon distension, as opposed to all of the patients with a diagnosis of diarrhea-predominant IBS. In contrast, patients with Crohn’sdiseaseshowhigherthresholdsfor aversivesensations in response to slow ramp distensionof the rectum, and markedly reduced systemic autonomic activation. However, atypical viscerosomatic referral patterns, a decreasedrate of receptiverelaxationand an increasedreflexresponseto stimulationof anal afferents are shared findingsin both patient groups. Evidence for decreased perception of rectal aversive stimulation in Crohn’spatients

Two complementaryhypotheseshave been proposed to explain the decreased sensitivityof chronic pain patients to acute painful stimuli.According to the adaptation leveltheory (Helson, 1964),chronic pain patients judgeadditionalpainfulstimuliin the contextof chronic pain as relativelymild. Similarly,it has been suggested that in patients who have undergone repeated instrumentationor surgery,thresholdsfor discomfortare set higherthan in subjectswho have not had this experience (Naliboff et al. 1981). The fact that higher thresholds for discomfort were only observed in responseto slowramp (but not to phasic)distension,and the fact that both patient groups have experiencedrepeated diagnostic evaluations argues against a pure psychological explanation. Another explanation for both the findingsof the current study and the somatic hypoalgesiapreviously reported in patients with IBS and Crohn’sdisease(Cook et al. 1987)is the activation of diffusenoxiousinhibitorycontrol systems(DNIC) by nociceptiveatTerentinput arising from the chronically irritated smallintestine(Le Bars et al. 1979;I-eBars and Dickenson 1979).It has previouslybeen shown in rats that acute nociceptivechemicalirritation of the viscera by intraperitonealinjectionof algesicsubstancessuchas bradykininor aceticacid (as wellas nociceptivesomatic stimuli)willlead to a reductionof the excitabilityof certain lumbar spinal neurons. Although originally for-

mulated to explain this so called heterotopic inhibition as a resultof an acutenoxiousstimulus,it was suggested to also underlie the higher sensitivity‘to acute pain in chronicpain patients (Le Bars and Willer 1988).For example,whilehyperalgesiacommonlydevelopsat the site of a noxious stimulus,increased thresholds to aversive stimuliin other parts of the body are commonlyfound in patientswith chronicpain (Peterset al. 1992;Ix Bars et al. 1979;Le Bars and Dickenson 1979). The observedincreaseof perceptionthresholdsin the current study was limited to sensations experiencedas aversive,regardlessof whether thresholdswere expressed with referenceto intrarectal pressure,volumeor wall tension.It has been shownin rats that DNICSappear to be restrictedto wide dynamic range neurons with convergentviscero-somaticinput (I-e Bars et al. 1979),as opposed to spinal neurons with exclusivelow or high thresholdinput (Le Barsand Dickenson1979),whichdo not show such inhibition. Thus, when the viscera are exposed to a noxious stimulus (such as intestinal transmuralinflamrnation), a pool of nociceptive,and of widedynamicrangespinalneuronswillbe excitedby the afferent input, while a larger pool of rostrocaudally located and of surroundingconvergentneurons will be inhibited. Furthermore, the response of these wide dynamicrange neurons to noxious stimuliinvolvingCfiberactivationis greatlyreduced,whilethe responseto innocuousinputs is lessaffected(hBars et al. 1979).If similar mechanismsare involved in the inhibition of visceralafferentinput, it is conceivablethat the perception of the innocuous sensation of stool is inhibited to a lesser degree than the noxious sensation of discomfort./pain.The fact that perception thresholds during ramp and phasic distensionwere atlxted differentially further supports the concept that these stimuli are encoded by different afferent mechanisms(Lembo et al. 1995), Eviakwcefor altered excitability of thoracolumbar spinal afferents in IBS and Crohn’spatients

Basedon resultsfrom experimentalanimals,it can be

158

assumedthat acute mucosalirritation involvingsignificant portions of a hollow viscuswill result in changes analogousto peripheral and central sensitizationat the correspondingsegmentallevelof the spinalcord (Mayer and Gebhart 1993).Even though sensory thresholds in the ileum were not determined in this study, lowered thresholdsto balloon distensionof the inflamedrectum in activeulcerativecolitishave been reported (LoennigBauckeet al. 1989;Farthing and Lennard-Jones 1978; Rao et al. 1988).All of our Crohn’sdiseasepatientshad ilealdisease,such that if hyperexcitabilityexistsin these patients,it would be at the levelof thoracolumbarspinal neurons. Whilethe increasedperceptionthresholdsin Crohn’s diseasepatientswere seen in responseto slowramp distension, the hypersensitivityin IBS patients, seen most clearly during the ascending distension protocol was restricted to rapid phasic stimuli. These observations suggest the possible involvementof different afferent mechanismsin the two patient groups.We have recently providedevidencefor the preferentialactivationof lumbar splanchnicpathways by phasic stimuli,and for the involvementof these afferents in the rectal hypersensitivityobservedin IBSpatientsduring phasicrectal distension (Lembo et al. 1994).It is traditionally assumed that the receptivefieldsof sympatheticafferents innervating the colon have their receptivefieldsprimarily in the mesentery,have high thresholds,do not accurately encode wall tension but do respond to traction on the mesentery(Leek 1977;Bessouand Perl, 1966).Evidence to support the concept of stimulus-specificactivationof differentvisceralatTerentshas been reported previously (Hurst 1911). One could speculate that DNICS in Crohn’sdiseasepatientsaffectpreferentiallywidedynamic range neurons in the sacral spinalcord receivingafferentinput from rectal tensionreceptors.In contrast to the majority of Crohn’s diseasepatients who had normal thresholds, only 3 patients were hypersensitiveto phasic distension. These patients viewed their gastrointestinal problem as more severe (mean VAS score 8) than the other Crohn’s diseasepatients (mean VAS score 5,5). Based on the observation that they showednormal perception thresholdsduring ramp distension (as opposed to the elevated ramp thresholds in the other 9 Crohn’s disease patients), it is conceivable that thesepatientshave a comorbidconditionof IBS, or that inadequate activation of DNICS had occurred. Despitethe normal perceptionthresholdsto phasic distension, indirect evidenceis consistent with altered excitability of certain spinal neurons which is shared by both IBS and Crohn’s disease patients. Abnormal viscerosomaticreferral of rectal distensionwas common in both IBSand Crohn’sdiseasepatients,and can be explainedas a reflectionof recruitmentof subthresholdafferent inputs to se~sitizedthoracolumbar dorsal horn

neurons receiving convergent viscero-somatic input (Mayer and Gebhart 1993). Differences in autonomic activation

It has previously been suggested that IBS patients when comparedto normal control subjectsshowhigher sympatheticnervoussystem(SNS) activityand increased SNS-mediatedresponsesto environmentalstressors (Fieldingand Regan 1984;Welgan et al. 1985;Welgan et al. 1988).Welgan et al. (1988) showed that even thoughIBSpatientsshoweda greater autonomicactivation of sigmoid motor activity to laboratory-induced anger, the increasewas fully accounted for by a greater emotionalresponse.A recentstudy by Payne et al. comparingIBSpatientswith age-and sex-matchedgroupsof normal controls and patients with inflammatory bowel disease showed no differences in the SNS response (measuredin the form of skin resistancelevels,skin temperature and heart rate) to two types of mental stress and to the cold pressor test (Payne et al. 1992). In Payne’sstudy no detailsabout the severityof diseasein IBD patientsor about the type of IBD (Crohn’sdisease vs. Ulcerativecolitis)were given.In contrast, the results of the current study,usingthe same outcomeparameter as Payne demonstrate that patients with IBS and IBD differin their SNS responseto a visceralstimuluswhich is perceivedas aversive. Thus, the normal discomfort thresholdsto phasic distensionseen in Crohn’s disease patientswasassociatedwith a blunted SNS response.In contrast, IBS patients not only report discomfort at a lower rectal pressure when compared to normals or Crohn’spatients,but the majorityof IBS patients showed a markedlyincreasedSNS responseat lower distensionrectalpressures.It has previouslybeen shownin the cat that sudomotorreflexesresponsesto visceraldistension are mediated by spinal reflexes (Jaenig and McLachlan 1987).In these experiments, the response wasmeasuredin the distributionof the same spinal segment as the siteof stimulation.However,it is likelythat the sudomotor reflex response of the upper extremity seen in the current study in response to stimulation of the rectum is likelyto involvesupraspinalsites, such as the locus coeruleus (Svensson 1987).It has previously been shown in the rat that locus coeruleusneurons are activated by visceraldistension, and that activation is most pronouncedin responseto rapid phasicdistension as opposed to slow ramp distension(Ekun et al. 1986). Rejlex regulation of rectum and anal sphincters In view of a previous report demonstrating that IBS patients have a normal resting tone of the descending colon,the findingsof this study suggestthat the reduced rate of rectal relaxationin responseto activedistension

159

represents an altered reflex response involving rectal mechanoreceptors.Even though the precise pathways underlyingrectal receptiverelaxation are not known, it can be assumed that in analogy to the stomach both intrinsic and extrinsic reflexes may play a role (Szurszewskiand King 1989).If spinalreflexesinvolving preganglionicsympatheticmotility regulating neurons as previously described in the cat (Bahr et al. 1986; Bartel et al. 1986;Gillis et al. 1989)play a role in the mediation of receptiverelaxation in response to rectal balloondistensionin humans,the reducedrate of receptive relaxation observed in both patient populations could result from increased excitability of certain motility regulating neurons in the hunbar spinal cord resultingeither from alteration in descendingcontrol or from central sensitization. The concept of altered function of lumbar motility regulatingneuronsin both patient groupsis further suggested by the observation that resting pressureswithin the anal canal and the reflexincreasein anal canal pressure during stimulation of the anal mucosal skin were significantlyhigher in both Crohn’s disease and IBS patients when compared to normals. The resting pressure within the anal canal is regulated by the myogenic tone of the IAS, by tonic influences of sympathetic postganglionicfiberson the IAS, and by tonic influence of the pudendalmotomeurons on the EAS (Krier 1989). Reflexincreasesin IAS tone can result from activation of lumbar splanchnic outflow in response to anal atTerentstimulation by shearing forces as used in this study (Bahr et al. 1986;Bartel et al. 1986),Since our recordingtechniquedid not allowmeasurementof activities of EAS and IAS separately, several alternative explanationsof our findingsare possible.Sinceboth patient groups experiencefrequent urgency and diarrhea, the increasedresting and squeezepressuresmay simply reflecta learnedresponseof the EAS to preventepisodes of fecal incontinence. Ins ummary, our findingsdo not support the mechanism outlined in hypothesis 1, which states that chronically recurrent ileal inflammation will result in sensitizationof thoracohurtbarafTerentsand associated rectal hyperrtlgesia.However,we provide evidencesuggesting that chronic ileal inflammation is associated with altered function of certain splanchnic afferent pathways,and alterations in reflex regulationinvolving sacral tierents and sympatheticregulationof anorectal motor activity. Together with the previously reported decreasedpain sensitivityto somatic stimuliin patients with Crohn’s disease,our ftndingsprovide evidenceto support hypothesis2, which states that chronic visceral inflammationwillresultin the activationof endogenous pain inhibition systems. While some of the observed alterations in afferent function are similar to those observedin IBS patients, significantdifferencesin per-

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