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5-Hydroxytryptamine Andhuman Small Intestinal Motility

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496 Gut 1994; 35:496-500 5-Hydroxytryptamine and human small intestinal motility: effect ofinhibiting 5-hydroxytryptamine reuptake D A Gorard, G W Libby, M J G Farthing Abstract nature is poorly understood.'0 In animals, Parenteral 5-hydroxytryptamine stimulates migrating motor complex cycling can be small intestinal motility, but the effect of con- modified by administration of 5-HT, its pre- tinuous stimulation with 5-hydroxytryptamine cursor 5-hydroxytryptophan, and its antago- on the human migrating motor complex is nists." '4 The effect of 5-HT on the migrating unknown. Using a selective 5-hydroxytrypta- motor complex in humans has not been studied. mine reuptake inhibitor, paroxetine, this study Tachyphylaxis to 5-HT given intravenously,45 investigated the effect of indirect 5-hydroxy- and associated cardiovascular and pulmonary tryptamine agonism on fasting small responses limit prolonged infusion of 5-HT in intestinal motility and transit. Eight healthy humans. The effect, however, of 5-HT agonism subjects were studied while receiving paroxe- on human small intestinal motor function might tine 30 mg daily for five days and while receiv- be alternatively investigated using a selective ing no treatment, in random order. Ambulant 5-HT reuptake inhibitor. Paroxetine selectively small intestinal motility was recorded from five inhibits the neuronal reuptake of 5-HT, increas- sensors positioned from the duodenojejunal ing the availability of synaptic 5-HT. Its ability flexure to the ileum for 16-18 hours. Paroxe- to inhibit 5-HT reuptake exceeds its ability to tine reduced the migrating motor complex inhibit noradrenaline reuptake by a factor of periodicity mean (SEM) from 81 (6) min to 67 320," making it four to five hundred times (4) min (p<005), and increased the propaga- as selective as the standard tricycic anti- tion velocity of phase III from 3-1 to 4-7 cm/ depressants imipramine and amitriptyline. min in the proximal jejunum (p<0-01), and Unlike traditional tricyclic drugs, paroxetine has from 1-6 to 3-4 cm/min distally (p<0-001). negligible affinity for muscarinic cholinergic Orocaecal transit time measured by lactulose receptors and does not bind at other neurotrans- hydrogen breath test was reduced by paroxe- mitter receptor sites. Although paroxetine is tine from 70 (9) min to 48 (7) min (p<005). used for its action in the central nervous system, These data suggest that 5-hydroxytryptamine enteric 5-HT neurones resemble central 5-HT participates in the control of migrating motor neurones in their response to 5-HT reuptake complexes in humans, and that selective 5- inhibitors.'6 The aim of this study was to use the hydroxytryptamine reuptake inhibitors have a 5-HT reuptake inhibitor paroxetine as an prokinetic action in the human small intestine. indirect 5-HT agonist, to examine the longer (Gut 1994; 35: 496-500) term effects of 5-HT on human small intestinal motility and transit. The gastrointestinal tract is the main source of 5- hydroxytryptamine (5-HT) in humans. In the Methods small intestine, 5-HT is found predominantly Eight healthy volunteers (five men, median age within the enterochromaffin cells of the mucosa, 25 years, range 23-33) without history of gastro- but significant amounts of 5-HT are also found intestinal symptoms or surgery were studied. within the myenteric plexus. In addition to its Each had small intestinal motility and transit role in the intestinal secretion of water and studies while receiving no treatment and while electrolytes, and its influence on mesenteric taking paroxetine in a randomised order. For the blood flow, 5-HT has prominent effects on paroxetine studies, a single daily dose of 30 mg intestinal motility. There is compelling evidence oral paroxetine was taken for five days. The that 5-HT is a neurotransmitter within the transit and motility studies were performed on enteric nervous system.'2 Enteric serotonergic the fourth and fifth days respectively. Drug free neurones are interneurones, innervating (control) studies and those where paroxetine was All Department of ganglion cells of the submucosal and myenteric given were separated by at least three weeks. Gastroenterology, St plexuses. subjects gave written informed consent and the Bartholomew's Hospital, 5-HT given intravenously over short periods study was approved by the research ethics com- London of the and Health District. D A Gorard of time has been shown to alter human small mittee City Hackney G W Libby intestinal motility-7 although such studies pre- M J G Farthing dated the recognition of the migrating motor Correspondence to: complex in humans.8 The migrating motor com- SMALL INTESTINAL MOTILITY Dr D A Gorard, Department of Gastroenterology, plex is a distally migrating pattern of motility Small intestinal motility was recorded using St Bartholomew's Hospital, seen during the fasting state in mammals.9 The a fine (2-7 mm diameter) flexible catheter West Smithfield, London EC1A 7BE. migrating motor complex is programmed by the incorporating five miniature electronic strain Accepted for publication circuitry of the enteric nervous system, but the gauge transducers (Gaeltec Ltd, Isle of Skye, 9 August 1993 oscillatory mechanism controlling its cyclical UK). The transducers were sited at 3 cm, 48 cm, 5-Hydroxytryptamine andhuman smallintestinal motility: effectofinhibitingS-hydroxytryptamine reuptake 497 68 cm, 83 cm, and 98 cm from the distal tip ofthe contractile activity. Migrating motor complex catheter. Fasting subjects were nasally intubated cycle length or periodicity was defined as the with the catheter at 0900. The tip of the catheter time interval between the onset of successive was guided through the pylorus using fluoro- phase III fronts occurring at site jI in the scopy, and a small balloon attached to the tip was proximal jejunum. This site was used for calcula- inflated with air to facilitate the propagative tion of periodicity, as phase III fronts occur activity of the intestine in pulling the catheter maximally in the proximal jejunum."7 Propaga- distally. Distal migration of the catheter con- tion velocity of phase III between adjacent tinued until the most proximal transducer was sensors was calculated by dividing the distance sited at the duodenojejunal flexure (site DJ) and between sensors by the time taken to pass from the other four transducers were 15 cm (site JI), one sensor to the next. The duration of each 30 cm (site J2), 50 cm (site J3), and 95 cm (site I) activity front at each sensor was measured from distal to the duodenojejunal flexure. The balloon the onset of regular contractions to quiescence. was then deflated, any redundant catheter was The maximum contractile rate during phase III withdrawn from the stomach, and the catheter at each site was determined. The extent to which secured to the face with tape. Recording of small each phase III migrated aborally, and the per- intestinal motility then began, with pressure centage of phase III fronts originating at sites sampling occurring at 8 Hertz. Data were stored beyond site JI were noted. digitally in a portable lightweight recorder A motility index for non-phase III - that is, (7-MPR recorder, Gaeltec Ltd, Isle of Skye, combined phase I and II - activity in the proximal UK) carried in a holster over the subject's jejunum (site JI), was calculated using computer shoulder. assisted analysis. Motility index was calculated Motility was recorded for 16-18 hours during as: which subjects were ambulant but discouraged from taking vigorous exercise because intense mean amplitude ofcontraction (mm Hg)xmean duration (min)x no ofcontractions physical activity masks the intestinal intra- time (min) luminal pressure recording with external pres- This analysis excluded contractile waves <15 sure artefact. Subjects spent the rest of the day mm Hg above the current baseline, which might and night at home and returned the next morn- represent respiratory excursion. Simultaneous ing. They were not allowed to eat, but were brief contractions seen at all sensors as a result permitted small amounts of clear fluids, which of artefacts such as coughing were similarly were recorded. When each recording was com- excluded from analysis. pleted, data were transferred from the 512 Kbyte Characteristics of migrating motor complexes memory of the recorder to a computer for recorded during the day were compared with graphic display and analysis. those occurring at night (2300-0500). ANALYSIS OF MOTILITY OROCAECAL TRANSIT TIME Figure 1: Motility recording Motility data were analysed without knowledge On a separate occasion, orocaecal transit time from thefive small intestinal of whether control or paroxetine recordings was determined after an overnight fast and a 20 sites. Phase III activityfront Contractile patterns were ml mouthwash with 0-2% wt/vol chlorhexidine ofthe migrating motor were being studied. complex propagates distally, analysed visually (Fig 1). The activity front or gluconate. End expiratory breath samples were preceded by irregularphase phase III of the migrating motor complex was analysed before and at 10 minute intervals after II activity andfollowed by recognised as at least three minutes of uninter- ingestion of20 ml (13 4 g) lactulose for hydrogen quiescence ofphase I. Site DJ represents pressure at the rupted phasic contractions at the maximum rate concentration (Hydrogen monitor, GMI duodenojejunalflexure, sites for that intestinal site, followed by motor quies- Medical Ltd, Renfrew, UK). Orocaecal transit J1 J2' J3, and I represent cence (phase I). Phase II consisted of irregular time was defined as the period of time between pressure at 15 cm, 30 cm, 50 and 95 cm aborally. lactulose ingestion and a sustained (>10 ppm cm, above baseline) rise in breath hydrogen. STATISTICAL ANALYSIS Site DJ Data are expressed as mean (SEM). Statistical significance was assessed using analysis of Site J, variance, and Student's t tests for paired and unpaired data. SiteJ2 Results Eighty one complete migrating motor complexes SiteJ3 were recorded while subjects were drug free (control), and 102 complete migrating motor complexes were recorded while subjects received paroxetine.
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