Gut 1994; 35:496-500

5-Hydroxytryptamine and human small intestinalmotility: effect of inhibiting 5-hydroxytryptaminereuptake

D A Gorard, GW Libby, M J G Farthing

AbstractParenteral 5-hydroxytryptamine stimulatessmall intestinal motility, but the effect of con-tinuous stimulation with 5-hydroxytryptamineon the human migrating motor complex isunknown. Using a selective 5-hydroxytrypta-mine reuptake inhibitor, paroxetine, this studyinvestigated the effect of indirect 5-hydroxy-tryptamine agonism on fasting smallintestinal motility and transit. Eight healthysubjects were studied while receiving paroxe-tine 30 mg daily for five days and while receiv-ing no treatment, in random order. Ambulantsmall intestinal motility was recorded from fivesensors positioned from the duodenojejunalflexure to the ileum for 16-18 hours. Paroxe-tine reduced the migrating motor complexperiodicity mean (SEM) from 81 (6) min to 67(4) min (p<005), and increased the propaga-tion velocity of phase III from 3-1 to 4-7 cm/min in the proximal jejunum (p<0-01), andfrom 1-6 to 3-4 cm/min distally (p<0-001).Orocaecal transit time measured by lactulosehydrogen breath test was reduced by paroxe-tine from 70 (9) min to 48 (7) min (p<005).These data suggest that 5-hydroxytryptamineparticipates in the control of migrating motorcomplexes in humans, and that selective 5-hydroxytryptamine reuptake inhibitors have aprokinetic action in the human small intestine.(Gut 1994; 35: 496-500)

nature is poorly understood.'0 In animals,migrating motor complex cycling can bemodified by administration of 5-HT, its pre-cursor 5-hydroxytryptophan, and its antago-nists." '4 The effect of 5-HT on the migratingmotor complex in humans has not been studied.Tachyphylaxis to 5-HT given intravenously,45and associated cardiovascular and pulmonaryresponses limit prolonged infusion of 5-HT inhumans. The effect, however, of 5-HT agonismon human small intestinal motor function mightbe alternatively investigated using a selective5-HT reuptake inhibitor. Paroxetine selectivelyinhibits the neuronal reuptake of 5-HT, increas-ing the availability of synaptic 5-HT. Its abilityto inhibit 5-HT reuptake exceeds its ability toinhibit noradrenaline reuptake by a factor of320," making it four to five hundred timesas selective as the standard tricycic anti-depressants imipramine and amitriptyline.Unlike traditional tricyclic drugs, paroxetine hasnegligible affinity for muscarinic cholinergicreceptors and does not bind at other neurotrans-mitter receptor sites. Although paroxetine isused for its action in the central nervous system,enteric 5-HT neurones resemble central 5-HTneurones in their response to 5-HT reuptakeinhibitors.'6 The aim of this study was to use the5-HT reuptake inhibitor paroxetine as anindirect 5-HT agonist, to examine the longerterm effects of 5-HT on human small intestinalmotility and transit.

Department ofGastroenterology, StBartholomew's Hospital,LondonD A GorardGW LibbyM J G FarthingCorrespondence to:Dr D A Gorard, Departmentof Gastroenterology,St Bartholomew's Hospital,West Smithfield, LondonEC1A 7BE.Accepted for publication9 August 1993

The gastrointestinal tract is the main source of 5-hydroxytryptamine (5-HT) in humans. In thesmall intestine, 5-HT is found predominantlywithin the enterochromaffin cells of the mucosa,but significant amounts of 5-HT are also foundwithin the myenteric plexus. In addition to itsrole in the intestinal secretion of water andelectrolytes, and its influence on mesentericblood flow, 5-HT has prominent effects onintestinal motility. There is compelling evidencethat 5-HT is a neurotransmitter within theenteric nervous system.'2 Enteric serotonergicneurones are interneurones, innervatingganglion cells of the submucosal and myentericplexuses.5-HT given intravenously over short periods

of time has been shown to alter human smallintestinal motility-7 although such studies pre-dated the recognition of the migrating motorcomplex in humans.8 The migrating motor com-plex is a distally migrating pattern of motilityseen during the fasting state in mammals.9 Themigrating motor complex is programmed by thecircuitry of the enteric nervous system, but theoscillatory mechanism controlling its cyclical

MethodsEight healthy volunteers (five men, median age25 years, range 23-33) without history of gastro-intestinal symptoms or surgery were studied.Each had small intestinal motility and transitstudies while receiving no treatment and whiletaking paroxetine in a randomised order. For theparoxetine studies, a single daily dose of 30 mgoral paroxetine was taken for five days. Thetransit and motility studies were performed onthe fourth and fifth days respectively. Drug free(control) studies and those where paroxetine wasgiven were separated by at least three weeks. Allsubjects gave written informed consent and thestudy was approved by the research ethics com-mittee of the City and Hackney Health District.

SMALL INTESTINAL MOTILITYSmall intestinal motility was recorded usinga fine (2-7 mm diameter) flexible catheterincorporating five miniature electronic straingauge transducers (Gaeltec Ltd, Isle of Skye,UK). The transducers were sited at 3 cm, 48 cm,

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5-Hydroxytryptamine and human small intestinal motility: effectofinhibitingS-hydroxytryptamine reuptake

68 cm, 83 cm, and 98 cm from the distal tip of thecatheter. Fasting subjects were nasally intubatedwith the catheter at 0900. The tip of the catheterwas guided through the pylorus using fluoro-scopy, and a small balloon attached to the tip wasinflated with air to facilitate the propagativeactivity of the intestine in pulling the catheterdistally. Distal migration of the catheter con-tinued until the most proximal transducer wassited at the duodenojejunal flexure (site DJ) andthe other four transducers were 15 cm (site JI),30 cm (site J2), 50 cm (site J3), and 95 cm (site I)distal to the duodenojejunal flexure. The balloonwas then deflated, any redundant catheter waswithdrawn from the stomach, and the cathetersecured to the face with tape. Recording of smallintestinal motility then began, with pressuresampling occurring at 8 Hertz. Data were storeddigitally in a portable lightweight recorder(7-MPR recorder, Gaeltec Ltd, Isle of Skye,UK) carried in a holster over the subject'sshoulder.

Motility was recorded for 16-18 hours duringwhich subjects were ambulant but discouragedfrom taking vigorous exercise because intensephysical activity masks the intestinal intra-luminal pressure recording with external pres-sure artefact. Subjects spent the rest of the dayand night at home and returned the next morn-ing. They were not allowed to eat, but werepermitted small amounts of clear fluids, whichwere recorded. When each recording was com-pleted, data were transferred from the 512 Kbytememory of the recorder to a computer forgraphic display and analysis.

ANALYSIS OF MOTILITYMotility data were analysed without knowledgeof whether control or paroxetine recordingswere being studied. Contractile patterns wereanalysed visually (Fig 1). The activity front orphase III of the migrating motor complex wasrecognised as at least three minutes of uninter-rupted phasic contractions at the maximum ratefor that intestinal site, followed by motor quies-cence (phase I). Phase II consisted of irregular

Site DJ

Site J,

SiteJ2

SiteJ3

Site I

50 mm Hg

5 min

contractile activity. Migrating motor complexcycle length or periodicity was defined as thetime interval between the onset of successivephase III fronts occurring at site jI in theproximal jejunum. This site was used for calcula-tion of periodicity, as phase III fronts occurmaximally in the proximal jejunum."7 Propaga-tion velocity of phase III between adjacentsensors was calculated by dividing the distancebetween sensors by the time taken to pass fromone sensor to the next. The duration of eachactivity front at each sensor was measured fromthe onset of regular contractions to quiescence.The maximum contractile rate during phase IIIat each site was determined. The extent to whicheach phase III migrated aborally, and the per-centage of phase III fronts originating at sitesbeyond site JI were noted.A motility index for non-phase III - that is,

combined phase I and II - activity in the proximaljejunum (site JI), was calculated using computerassisted analysis. Motility index was calculatedas:mean amplitude of contraction (mm Hg)xmean duration (min)x no of contractions

time (min)

This analysis excluded contractile waves <15mm Hg above the current baseline, which mightrepresent respiratory excursion. Simultaneousbrief contractions seen at all sensors as a resultof artefacts such as coughing were similarlyexcluded from analysis.

Characteristics of migrating motor complexesrecorded during the day were compared withthose occurring at night (2300-0500).

OROCAECAL TRANSIT TIMEOn a separate occasion, orocaecal transit timewas determined after an overnight fast and a 20ml mouthwash with 0-2% wt/vol chlorhexidinegluconate. End expiratory breath samples wereanalysed before and at 10 minute intervals afteringestion of20 ml (13 4 g) lactulose for hydrogenconcentration (Hydrogen monitor, GMIMedical Ltd, Renfrew, UK). Orocaecal transittime was defined as the period of time betweenlactulose ingestion and a sustained (>10 ppmabove baseline) rise in breath hydrogen.

STATISTICAL ANALYSISData are expressed as mean (SEM). Statisticalsignificance was assessed using analysis ofvariance, and Student's t tests for paired andunpaired data.

ResultsEighty one complete migrating motor complexeswere recorded while subjects were drug free(control), and 102 complete migrating motorcomplexes were recorded while subjects receivedparoxetine. Overall migrating motor complexperiodicity at the proximal jejunum (site JI) was81 (6) min during the control study, and 67 (4)min while receiving paroxetine (p<005). Thenormal shortening of migrating motor complexperiodicity at night"a occurred during controland paroxetine studies. Migrating motor com-

Figure 1: Motility recordingfrom thefive small intestinalsites. Phase III activityfrontofthe migrating motorcomplex propagates distally,preceded by irregularphaseII activity andfollowed byquiescence ofphase I. SiteDJ represents pressure at theduodenojejunalflexure, sitesJ1 J2' J3, and I representpressure at 15 cm, 30 cm, 50cm, and 95 cm aborally.

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5-

4--EC.)E

C._o

0

0

C_0)Q0CDa0

120

100Paroxetine

DJ-J 1 J1-J2 J2-J3 J3-l

SiteFigure 2:.Propagation velocity ofphase III between adjacent pairs ofsensors while receiving nodrug (control) and paroxetine. Site DJ duodenojejunalflexure, sites _J1, 72, J3jejunum, site Iileum. *p<O-01 compared with control velocity; **p<0-001 compared with control velocity.

-

6-

aCU

DJ JA J2 J3

SiteFigure 3: Duration ofphase III at each recording site while taking no drug (control) andparoxetine. Site DJ duodenojejunalflexure, sitesJII, J72,J3jejunum, site I ileum. *p<OO01compared with baseline duration.

plex periodicity in the control study was 93 (10)min diurnally, 68 (5) min nocturnally (p<005),and with paroxetine was 75 (6) min diurnally, 59(5) min nocturnally (p<005). While awake, theperiodicity of migrating motor complex cyclesduring which fluids were ingested did not differfrom the periodicity of cycles during whichsubjects were strictly fasted. The volume of clearfluid consumed during control recordings was420 (50) ml, and while receiving paroxetine was470 (40) ml.

Maximum contractile rate and mean amplitude ofphase III contractions at each small intestinalrecording site

Site DJr Site7, SiteJ2 Site73 Site IMaximum phase III contractile rate

Baseline (contractions/min) 11-0 (0-2) 10-8 (0-1) 10-6 (0-2) 10-2 (0-1) 9-9 (02)Paroxetine (contractions/min) 11-1 (0-1) 10-9 (0-2) 10-5 (0-1) 10-2 (0-1) 9-8 (0-3)

Mean phase III amplitudeBaseline (mm Hg) 35-1 (2 2) 32-3 (1-8) 34-6 (2-1) 34-3 (1-8) 41-3 (2-1)Paroxetine (mm Hg) 33 0 (1-5) 32-7 (1-5) 33-7 (1-4) 32-5 (1-0) 38-8 (1-9)

Data represent mean (SEM). Site DJ represents sensor at duodenojejunal flexure, sites JI, J2, J3, andI represent sensors at 15 cm, 30 cm, 50 cm, and 95 cm aborally.

'EC.)

C._

0EcJ,o

li

80-

60-

40-

20-

0-Control Paroxe

Figure 4: Orocaecal transit time while receiving no drug(control) and while taking paroxetine.

etine

PHASE III CHARACTERISTICSAs phase III activity fronts progressed aborally,their propagation velocity decreased, a findingconsistent with reports from other workers."719The propagation velocity of phase IIls betweenpairs of adjacent sensors was increased byparoxetine (Fig 2). Paroxetine increased thepropagation velocity from 3-1 to 4-7 cm/min inthe proximal jejunum (p<001), and from 1-6to 3-4 cm/min distally (p<0001). During thecontrol study, the time duration for which phaseIIIs were recorded at each successive sensorincreased with distal propagation (Fig 3).During the paroxetine study, the faster propa-gating phase IIIs were present at all the sensorsfor a shorter duration of time (p<001).The maximum contractile frequency within

phase III decreased with aboral propagation ofphase III, and was unaffected by paroxetine(Table). The mean amplitude of phase IIIcontraction was not influenced by paroxetine(Table). Phase III amplitude recorded in theileum with and without paroxetine was greaterthan phase III amplitude recorded more proxi-mally.

During the control recording, 24% of phaseIII activity fronts recorded at site DJ and migrat-ing to at least the next two sensors, J2, failed toreach the most distal recording site in the ileum,site I. While receiving paroxetine a similarproportion, 21% of phase III fronts failed topropagate as far as site I. During the controlstudy, 6% of phase III activity fronts originatedat site J2 or J3 and were recorded at a minimumof two consecutive sensors. While receivingparoxetine a similar proportion, 9% of phase IIIfronts started this far distally.

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NON-PHASE III MOTILITY INDEXDuring the day, the motility index for non-phaseIII activity was not different during the controlstudy, 6 8 (2 2), and the paroxetine study, 4-2(1 1). At night the motility index for non-phaseIII activity was also similar during the controlstudy 2 4 (0 5), and the paroxetine study 2-0(0 4). These nocturnal motility indexes werelower (p<0 05) than the respective diurnalmotility indexes, a consequence of diminishedphase II activity at night.'8

OROCAECAL TRANSIT TIMEControl orocaecal transit time measured bylactulose hydrogen breath test was 70 (9) min(Fig 4). Paroxetine reduced orocaecal transittime to 48 (7) min (p<0 05).

DiscussionWe have shown that indirect 5-HT agonismusing a 5-HT reuptake blocker influences humansmall intestinal fasting motility and transit.Short term intravenous administration of 5-HTto humans is known to stimulate small intestinalcontractile activity.< Within minutes of intra-venous 5-HT, contractions occurring at a maxi-mal rate are seen in the jejunum.45 The effects of5-HT on migrating motor complex cycling,however, have been only studied in animals. Insheep, the 5-HT precursor 5-hydroxytrypto-phan decreases the periodicity of migratingmotor complex cycles." In the dog, intravenous5-HT causes increased small intestinal phasiccontractions.'2 The canine migrating motor com-plex may be replaced with continuous phase IIIlike contractions,20 particularly at high dosesof 5-HT.2' Low dose 5-hydroxytryptophandecreases migrating motor complex periodicityin rats, whereas a higher dose disrupts themigrating motor complex.'4 In the opossum,intravenously infused 5-HT decreases theperiodicity of migrating motor complexes in adose dependent manner, and increases the prop-agation velocity of phase III activity fronts.'3These animal studies suggest that 5-HT partici-pates in migrating motor complex cycling.Furthermore, selective destruction of 5-HTenteric neurones in the rat disrupts the migratingmotor complex.22

In this study, ambulant recordings of humansmall intestinal motility have shown that 5-HTagonism with paroxetine affects the humanmigrating motor complex. Migrating motorcomplex periodicity was decreased and the prop-agation velocity of phase III fronts was increasedby paroxetine. Although sleeving of the smallintestine over the catheter may lead to an under-estimate of calculated propagation velocity, thisis equally likely to have occurred in recordingswith and without paroxetine.The more frequent and faster propagating

migrating motor complexes were associatedwith a shortened orocaecal transit time. Usinglactulose alone to measure orocaecal transit timedoes not interrupt the fasting migrating motorcomplex pattern. This technique of measuringdrug induced differences of orocaecal transittime is perhaps more relevant to this study than

one using a test meal, because we were investi-gating drug induced differences of fastingmotility. Orocaecal transit time comprisesgastric emptying as well as small intestinal transittime. Liquids begin to empty from the stomachalmost immediately after ingestion, however,and orocaecal and duodenocaecal transit timesof lactulose are not different.23 Thus the decreasein orocaecal transit time by paroxetine cannot bea result of an increase in gastric emptying.Furthermore, studies using 5-HT,6 5-HT3antagonists,24 and 5-HT,p agonists/antagonists2suggest that 5-HT agonism may delay ratherthan promote gastric emptying. Therefore theshortening of orocaecal transit time by paroxe-tine truly reflects a shortened small intestinaltransit time. Whether paroxetine reduces smallintestinal transit in the fed state cannot beinferred from this study. Any similar prokineticeffect in the small intestine during the post-prandial state might be accompanied by a delayin the gastric emptying ofa solid meal induced by5-HT agonism.The possibility that paroxetine might be exert-

ing its effects on small intestinal motor activityby a non-serotonergic mechanism is remote.Radioligand binding studies show that paroxe-tine does not directly interact with al, a2, or ,adrenoceptors, dopamine, histamine or even5-HT receptor subtypes.'525 Although itdoes have very weak affinity for muscariniccholinergic receptors, any anti-muscarinic effectproduced by paroxetine might be expected toimpede migrating motor complex cycling26 lead-ing to lengthening of migrating motor complexperiodicity2' and delayed orocaecal transittime.28 Equally paroxetine's weak inhibitionof noradrenaline reuptake and consequentincreased availability of synaptic noradrenalineis unlikely to account for the changes seenin small intestinal motility and transit. Stimula-tion of al and f adrenoceptors leads to anincrease rather than a decrease in orocaecaltransit time2930 while the prolongation oforocaecal transit time by a2 receptor stimulationis not significant.3'The nature of this study precludes precise

identification of the site of 5-HT action or the5-HT receptor subtype(s) that are responsible.Paroxetine acts centrally to achieve its effect onmood. Serotonergic neurones of the entericnervous system resemble those of the centralnervous system, however, and are similarlyaffected by reuptake inhibitors. 16 In sheep,reduction in migrating motor complex period-icity by methysergide was unchanged by section-ing the extrinsic nerve supply to the gut." Thissuggests that pharmacological manipulationsof the migrating motor complex with 5-HTagonists/antagonists given systemically occur atthe level of the enteric nervous system.

If it is assumed that paroxetine's effects onsmall intestinal motility and transit are a result ofits actions on the enteric nervous system, we canonly speculate as to which stimulated 5-HTreceptor subtype(s) is involved. Of the knownsubtypes, 5-HTIA, 5-HT,p, 5-HT3, and 5-HT4receptors have been identified in the entericnervous system. In rats there is some evidencethat 5-HT3 receptors participate in migrating

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motor complex cycling, because a 5-HT3receptor antagonist prolongs the periodicity ofjejunal migrating motor complexes.'4 In dogs,5-HT3 receptor antagonism has no effect onjejunal migrating motor complexes3233 butinhibits gastric and duodenal phase III.32 Inhumans 5-HT3 receptor antagonism does notaffect duodenal migrating motor complexes,34or small intestinal transit time.3536 Thereforethese human studies do not support a role for5-HT3 receptors in controlling the migratingmotor complex in humans. Most in vivo studies,however, of healthy subjects with 5-HT1 like,5-HT2, and 5-HT3 receptor antagonists fail toshow any dramatic effects on motility,37 suggest-ing that 5-HT may have a rather subtle modula-tory function in health.

In summary, this study has shown that 5-HTagonism leads to more frequent and fasterpropagating migrating motor complexes, andimplicates the participation of 5-HT in thecontrol of human migrating motor complexcycling. The accelerated orocaecal transit timeproduced by 5-HT reuptake inhibition suggeststhat selective 5-HT reuptake inhibitors may havea prokinetic use in disorders of small intestinaltransit.

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6 Misiewicz JJ, Waller SL, Eisner M. Motor responses ofhumangastrointestinal tract to 5-hydroxytryptamine in vivo and invitro. Gut 1966; 7: 208-16.

7 Labo G, Barbara L, Lanfranchi GA, Bortolotti M, Miglioli M.Modification of the electrical activity of the human intestineafter serotonin and caerulein. AmJ Dig Dis 1972; 17: 363-72.

8 Vantrappen G, Janssens J, Heilemans J, Ghoos Y. Theinterdigestive motor complex of normal subjects andpatients with bacterial overgrowth of the small intestine.J Clin Invest 1977; 59: 1158-66.

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17 Kellow JE, Borody TJ, Phillips SF, Tucker RL, Haddad AC.Human interdigestive motility: variations in patterns fromesophagus to colon. Gastroenterology 1986; 91: 386-95.

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23 Di Lorenzo C, Dooley CP, Valenzuela JE. Role of fastinggastrointestinal motility in the variatility of gastrointestinaltransit time assessed by hydrogen breath test. Gut 1991; 32:1127-30.

24 Akkermans LMA, Vos A, Hoekstra A, Roelofs JMM,Horowitz M. Effect of ICS 205-930 (a specific 5-HT3receptor antagonist) on gastric emptying of a solid meal innormal subjects. Gut 1988; 29: 1249-52.

25 Dechant KL, Clissold SP. Paroxetine. A review of its pharma-codynamic and pharmacokinetic properties, and therapeuticpotential in depressive illness. Drugs 1991; 41: 225-53.

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