gastrointestinal motility and

REVIEW

Opiate tnodulation of gastrointestinal motility and

the actions of tritnebutine

STFl'l lEN M CmLJNS, MB.BS, FRC P(UK) , FRCPC, EPWIN E l'lANll:1., Pl ID

SM COLLINS, EE DANIEL O piate modulat ion of gastroin testinal motility and the ac tio n s of trime butirne. Can J Gastroentero l 1991;5(5):185-193. Tri mebut ine is an opiate ligand that interacts with the µ, o anJ K receptor ,ubclasses with approximately equal affin ity. S ince opiate receptors arc wide ly distributed in the gut, and because opiate receptor subtypes may be invo lveJ in cxcitaLOry or inhibitory control mechanisms, trimebutine has an unusual profile of action that cannot be preJic ted on the basis of experience with other synthetic opiates such as codeine, morph ine or lopcramide. T ri mcbutinc influences motility th roughout the gasuninrestinal tract. The effect of t rimcbutine on the lower esophageal sphincter raises the possibi li ty of a benefic ia l ro le in the trearment of gastroesophagcal reflex disease. T he abi lity of trimebutine to promote propulsive activity in the fast ing and postprandia l sma ll intestine offers novel therapeutic approaches to the treatment of motility disorders, including postoperat ive ileus and r seudo-obstruct ion. Fina lly, the effect of the drug on the colon supports t he use of trimcbutine in irritable bowel synd rome pa tients who have constiration due to colonic inertia.

Key Words: GCL~ trointestinal motility , Muscle, Nerve, Opiates, PharrnacolDgy, Rece/nors , T rimebutine

Opiaces et motilite gastrointest inale - Les effets de la trimebutine

RESUME: La trimehut ine est un liganJ opiace qu i agit avcc une affinirc a pcu prc5 cga le a u n iveau Jes sous-types Je recepteurs µ, o ct K. Paree que les recepteurs opiaces abonden t dans l'intcstin et parce que les sous- types de recepteurs opiaces participent peut-etre aux mccanismes de regulation excitateurs ct inhibiteurs, la

lntesunal Disea.1e.1 Research Unir and Snwoth Mmcle l~esearch Pm1:rnm , De/wrrme1H1 of Medicine and 13iomedical Science, , McMasrer Urnversir:,· Medical Ccnr,e, I lamilwn. Onwrro

Crmes f)()rtc.k'nce and refmnr, : I )r liM Col/rm, /foom 3N5c, /nre,ri1w/ Di1eme.1 He,earch Cnrr, McMasrer Medical Ccncre, 1 lamrlwn , ( )nwrio L8N 325. Tdeflhonc ( 41 6) 525-9 I 40 ext 2586

Received for Jlublicarion Fein-um)' 25. 1991 Aece(>ted AttRUSL 15 , I 99 I

CAN J GA~'TRUENTl:.ROI V o 1 'i Nn 5 S E!'Tl·.MllER/(). , Ul\l:R J 9LJ I

T RIMEl\lJTINl: (2-DIMl.:TJ IYLAMIN0-2-

phcnylhut yl - trimcthoxybenzoatc mal cat e; M odulon, Jouv c in a l ) h ns hcen used to treat severa l manifcst,lt ion ~ o f functronal bowel d isease , rncl uding idiopat hic (nonulcer) dyspcp~ia (I) , ahdtirninal pain (2) and altered bowel hahi t~ (3 ). T he therapeu tic henefi t nf t rimehutine in these disorders is hcl ieved to he due to its effect on moti lity (4).

T he mechanism of action of t rimchutine has only recently become understood. 1 n 1987 in vitro~t uJies providcd defini t ive evidence that t rimebu t inc int ernc ts with opiate receptors in the hrnin and myenrcric plexus (5,6), and it is reasonahle to as~urnc that many of the act iom of t rimchutine on mot ili ty arc mediated by opiate receptors. In order 10 understand the effects of trimehutine on moti li ty, it i~ first necessary to review hricOy oriate receptor pharmacology, as wel I a~ some principle~ that unJcrl ie the control of gastrointestina l moti li ty .

OPI ATE RECEPTORS AND MOTILIT Y

C lassif icat io n of opia t e recepto rs: Natura lly occurring opiate pcpttde~ ,ire widely di~trihuted in the brain, ;wtonomic nervous system and gut , anJ in-

185

Ct)! I INS ,\Ni l D:\Nfl I

trimcbutinc prescnte un mccanisme <l'action qu'on ne pcut prcvmr d'aprcs !'experience qu'on a des autres opiaccs synrhctiqucs tcb quc la coJ cinc, la morphine ct la lopcramidc. La trimcbutine rcnforcc la morilitc <lcs voies Jige:,nves. Son cffct :,ur le sphincter oesophagicn inferieur laissc emrcvo ir un ro le bencfique Jans le traitement du reflux gastro-ocsophagicn. Le fair quc la trimchurine stimule la morricitc du grelc a jcun et apre:, lcs repas offn: <le nouvelle:.. po:..sibilit6 dam le tra itcment Jc:, troubles de la motilitc ilcus post-opcratoirc ct pseu<lo-obstruction, entrc aurrcs. Finalcmcnt, !'action du medicament sur le colon encourage a pre:;crirc la trimchutine aux patients souffranr Ju syndrome Ju colon irriwblc ct <le const ipation atone.

TABLE 1 The binding of ligands to opiate receptors in guinea pig brain and myenteric

lex us Brain DHM (p ) DADLE (6) EKC (IC)

T rimebutine 212±40 1747±245 1455±120 Dimethyl-trimebutine 345±90 1080±330 1372±157 Morphine 7±1 152±52 128±15 DADLE 8±1 1±0 2187±688 EKC 1±0 4±1 0.5±0 Myenteric plexus DAGO (p) DSLET (6) EKC (K)

Trimebutine 1609±389 1193±304 1803±378 Dimethyl-trimebutine 1924±708 2196±228 6152±1183 Morphine 7±1 578±178 330±39 DSLET 347±86 23±7 885±176 EKC 28±1

Shown ore the 50% Inhibitory concentration values (in nM) for the ability of various opiates to displace rodiollgonds from synopfosomes from gwneo pig brain or myenteric plexus. The rodioligonds ore shown on the horiZontol axis of the fop of the fable DADLE (D·Ald1-D-Le1}) enkephohn, o 6 selective llgond: DAGO (D·Alif-Mephe4-Glyof) enkepholin o µ -selective ligand. OHM D1hydromorphlne, o µ-selecf,ve ligand DSLEr (D Sef L-Leu"-L-Thr') enkepholln. o 6-select/ve ligand.· EKC Ethylketocyc/ozoc1ne. o 11: selecf1ve ligand

TABLE 2 Differences between trimebutine and morphine Qpiate selectivity Lower esophogeal sphincter pressure Normal colonic motility Colonic transit Clinical effect

cluJe met- and lcu-cnkephal in and Jynorphin (7-9). In the gut, rhcse peptides arc prc!>ent in nerves of the mycnterac and suhmucous plex use:.. ( 10,12). At least three distinct subclasses of opiate recepwrs have been idcnt ificd and arc termed µ, 8 and K

receptors on the basis nf their affinities for ·elective opiate lignnds. µ and 8 receptors arc usua lly linked tn tissue activation, whereas K receptors a rc often linkc<l to inhibitory syste1m. Morphine exh ibits se lectivity for µ rcceprors, whereas trimcbutine intcracb with

Trimebutine (p,6,K) Morphine <J:t) Increases Decreases No effect Stimulates Accelerates Regulates

Slows Constipates

µ, 8 and K receptors with almost equal affinity (5,6) (Tables l ,2). T hus, syn thetic opiates may differ suhsrantially in their effects on moti lity as a result of rheir profile of selectivity for recepwr subclasses. Sites of action of opiate-induced changes in motility: Opiate receptors that influence gastrointest inal motility nre present in the gutas ,veil as in the brain, spinal cord ( I 3) and auwnom ic gang I ia. The abi li ty of centra lly administered opiates to affect motility in animab ts well recognized.; intracerebroventricu-

lar administration of morphine mcrcascs myoclectrical spake ,Ktavity an the fc l inc small intestine ( 14 ), anJ delays intestinal tramit in the rat ( 15). Contro l is also cxcncJ ar the level of the spi na l cord and c1uronom1c ganglia, experiments in mice following trnnssection of the cord have demonstrated the rrcsence of spina l opiate receptors that mcdime c hanges in gastrointestinal mot ili t y ( 16). Opia tes also induct: changes in ne rve cclb in autonom1t ganglia wh ich receive input from ho1h the brain and periphery, and thus play an imponant integrative role in the control of gastrointestinal moti lity ( 17).

Receptors for opa.Hcs within the gut are locn 1ed primarily on entcnc neuron:.., a nd opiates influence motility primarily by modulating cntcnc neural acu vity. While 01w11c receptors have been 1Jentif1e<l on smooth muscle cells bolmed from the gut ( 18), It 1s uncertain whether they mediate np1atc-111-Juced motility responses 111 v ivo. Opiate:, may also mfluence mntalny hy altering the hormonal e nvironment 111

the gur. S tu<l1cs in the dog have shown that

opiates a lter the release of a variety of gut peptides, ear h cr via a neural mechanbm or by direct stimulauon of endocrine cells in the mucosa ( 19). Of parcicular importance is the ability of opiates to induce the release of motilm, a peptide which induces propagated mmor responses in the inrcstinc dunng t he interdigestivc state (20). It shoulJ he noted that these ,Ktions a re not mutually exclusive, and that moti lity response to an opiate nhscrved in \ 1,·o may reflect the net cffcu of several of these mechanisms. Factors that influence the actions of opiates on motility: In addition tn the intrinsic properties of the opiate (1c, se lec tivity for specific receptor sub, types), t he effect of an opia te on ga,tmintestinal motility will he affected hy several other factors. These arc important nor only in the context of therapy, but abo in the interpretation nf data derived from in vivo and in vitro studic, of the mechanisms of actions llf opiate ligands.

The swte of 1/te gw. T he I in al determinant of gastroin testinal motilny "

186 CAN J GASTRt)ENTEROL Vnt 5 N t) 5 SLl'1l:Ml\rn/0C'ft ) I\ER 1991

the contract ile ;,wtc of ;.momh mu~de

m the gut. Entenc ner\'c;, contain a

variety of ncurotransm111crs that m;1y

ultimately srimulate mu,cle comrac-

11011 or induce relaxa1 ion, and the net

effect of opioids on motor act ivity will

depenJ on the neurotrnn~mitter con

tent of the nerve. Thu~. an (lpiate-in

duceJ increase in mmor activity may

occur a~ ;i rc~uh nl Mimulation uf an excitatory nerve or from mhih1tion of

the release of a neurotransmitter that

relaxe~ smonrh muscle. An example of

this is found 1111 he ~mall intc~tinc of the

dog (2 J ). The admm1stn11 ion ofopiares,

with the except ion of dynorphin,

results in stimulation of motor act1v1ry,

presumably via p nr b recepLOrs. The

action is blocked by the neuronal hlod,

cr terrodotoxin and reduced by atro

pine, indicating th,n pan (if I he effec t

on motility is due to the activation nf

cholincrgic nerves (21 ). Since the

response was not completely abolished

by atropine, a more complex mccha

nbm is suspected. More recent wmk ha~ shown that mouli ty in the canine ~mall

intestine i~ abo under the tonic inhi

bitory effect of vasoact 1vc intestinal

peptide ( IP) (a neurotransmitter that

relaxes ~mooch muscle), anJ rh ,11 opiate~ supprcs;, VIP release (22) via

both ~t and b receptm~ (unpublished

Jara). Thus, the ohscrvcd net excitatnry

effect of opiate:, in rhi:, in:..tance b due

to both the activation llf excitatory ner

l'e~ and 1he , uppress1on of inh ibitnry

nerves.

The converse 1s also true: opiaLe- in

Juced suppression of motor acLivit y

may rc~ult from the inhihition of an

excitatory nerve or the activation of an

inhibitory nerve (directly or indirectly

hy withdrawal of inhibirnry modul,1 -

tion). The extent to which inhibitory

or excitatory effects arc seen will

depend no t o nly on the inLrin:..ic

properrie~ of the opiate but abo on whether the intestine is active or quies

cent. Effects mediated by inhihitory

nerves will only he apparent if the in

testine is active, and no effect of the

drug will be observed 111 rhe unstimulated stare.

Presence of gastroimesrinal Jiseme. If a d1~ease process al ters the function or Jistributi(>n of enteric nerve,, it is

rca:..nnahle to as,ume that the mo11l1ty

response to a drug :,uch as an opiate wi II hL· a ltl'red. It has heen shown, fm ex

ample, that the nH1ror response of the

sigmrnJ colon 10 exogenou~ opiare is

greatly exaggerated in the presence of active colni :.. (21 ). Altht)ugh the rncch

,mbm lllllkrlying thi:, ohservauon has

yet to he ddined, ll may reflect ,1ltera

t 1om 111 the dist r1hu11on and content nf ent.eric nen'l's ass()Clated \\'llh intl;im

mat(>ry howel di:..case (24,25). With

respect w fun c t 1nnal hnwd di,ea,e, a

similar phen\lmen1)() ha~ heen observed

with colonic motor rc;.pomcs to chole

cystokmin (26) and with the ga,rrocolic reflex (27), which 1:, believed w mvnlve (>pi ate recepwrs (2H). It foll\lws

that smce n drug may mduce qune dil

lcrcnt responses in healthy suhjecls

than in patients wnh disease,, then rhe

effects of the drug in par1cnrs arc nn1

necessarily predic1ahle on the has1s ll(

its action in healthy subjects. The point

will be illustrated later with trimchutine.

1-<oute of culmini.mmion of o/>raic. Because of the wide dbtrihut Illll of opiare

receptors that influence moril1ry, the

net effect of an adm mistered opiate wi 11 abo depend on ,1bdn y to cross the blood

brain barrier, the rourc nf administra

tion, and (in the ca~e uf in vitro expen

mcms) 1he structural integrity nf the

tissue under study. Orally o r intra

venously adm111isrered drugs ha\'e ,ic

cess to the hrnm provided they cmss the

blood brain barrier. Drugs delivered

close to the gu1 hy Inca! imra-anerial

injectitm will pnmarily ac t on s ites

within the gut wall, mcluJing intrinsic

nerves, muscle, blood vesseb and

mucosa[ cells. Drugs applied to mu~cle

strip preparations in vi t m will act on

intrinsic nerves and muscle. Thus, it b not surprising to observe differences be

tween the rcspomes to cen tral and peri

pheral administration of opia1es and

between mntiliry resporn,cs to opiates

aJministereJ in vivo and in vitro (29-31 ).

THE MECHANISMS OF ACTION OF TRIMEBUTINE

ON MOTILITY Overview: Results of radioligand h1nd

ing studies arc consistent with the

CANJ GASTRllENTFRm Vl11 5 No 5 SEl'TEMBER/Cx."ft)I\ER ]991

Opiates and motility

hypmhes1s I hni I rimd1ut111c 1s an op1<llC

ligand that mtcr,Kh with µ, Sand K

neural rcc1:ptors wnh s1mil.1r .iffmity

(6). Taken 111 coniunction w11 h dat.1

from physi()lngical ,r11d1c:s, these llnd

mgs are C\1nsistcnt with the nn11on that tnmehutine hd1ave, ,is a weak 11\111 ·

,elecuvc opiate ag01w,t. On I hL· h,1s1' nl

this profile, t()gt'thcr with rc,ul1, of 111

vivo experiment~ in anim<1ls ,m(I in

humans, rhe mot i I it y prntilc of I rnnc

hut inc (nnJ hence its ther;1pl:ut1c

pment in!) canno1 Ix· pred 1cted on the

basis of familiarity w1rh trad1t1nn,1 l ,yn

thetic opiates such as crnk mc and morph me. Morphtne and codeine arc more

sc lccuve for µ receptms, whereas

trimchutine interacts equally withµ, b ,md K' rCLCptms. Thus, while certrnn

motility effects may he shared (cg, 111-

duction of motor complexes 111 the

,mall 111testine ), ocher acu om may be

quite different (Table 2). rrom ,1 c lini

cnl viewpoint, morphine and C()demc

slow transit and cause comupation,

whcre.1s I nmehuu nc appears to ac

celerate transit and may therefore he

beneficial 111 the treatment of con:..1 ip,1-

tinn due tn colon IC menia.

Stud ies on the mechani:.m and locus of action of trimcbutine: In addition w the results (lf radiol igand hinding

,rudics de,cnhcd ahnve, th ere arc

several studies that descr1he th e

mcchan1s1m nf act ion of tnmcbutine.

Acwm at extrm.m: nerves. The in

ferior mcsenrcric gnnglton serve~ tn tn

tegrate nerve impulses from the central

nervous system and peripheral nerves.

!1 connects the central nervous system,

the celiac plexus ,md the gut via the

intermcscnteric, hypngnstric and lum bar colnni c nerves, and thus b srra tcgicnlly located LO influence

gastrointestinal motility. Neurotransmi;.s1on from prcganglionic neurons 1~

cholinergic but is modulated by opiate~

( 17). Studies in the rabbit have shown

that trimcbutinc ( I µ g/mL) exerts a bi

valent effect on this ganglion, prnduc-

111g e nhcr inhihnion of cholmerg1c

nerve activity or innia l exc1caunn fol

lowed by late inhilw1on, without in

fluencing rc~tm g me mbrane potential

(32). T hus trnnebutinc may influence

motility (both initial and long term ex-

187

COLLINS ANll DANIEi

C 100 0

~ c 0 V .. 0 E a' 0

C 100 .2 u ~ c 0 V .. 0 E ~ 0

t T 100 ug

t T. I

t 100 ug

t t 10 ug

lm in.

Figure I) Example.~ of effem of crimelmrine (T) on unsrimulaied ( quiet) anafield-stimukued intestine. Intra-arterial injecriorl, ofT arc ~lwttnt hy ,mow1, and doses are given in µg. Top l:"'Jfern of Ton quiet jejunum (]). Note rhe /)rolonged submaximal stimulation. Bottom Effects of T m1 field-~rimulmed ileum (I) . Nmc chc dose-dependent inh,hition [m,duced /,y different doses of T and the Jnnlcmged action of higher doses (from reference 34)

cita tion) hy modulating sympathetic tone in rhe gut hy v irtue nf its c1ctinn on the inferior mesenteric ganglion .

LC1cal actiC1m of tnmebwine in ihe gut. A recent study investigated the local actions of trimehutine on the gut wall hy o hservi ng changes in c ircular muscle contract ion following ad ministration of the drug at various sites in the canine gut (3 3). Trimehutine was given in sma ll holuses hy intrn-arterial inject ion in order co restrict tts action to the region perfu~ed by the artery. In the stomach, 1 rimehutine, like other opime agon ists, had no excitatory effect in the quiescent gu1 , but inhibited motility induced hy activ,llion of local (post gang lionic) c holinergic nerves. In the quiescent small intestine, trimehutine ( I 00 µ g) st imulated motili1 y (Figure I ),

188

and t he effect was reduced by the neuronal blocker tetrodmoxin o r by atropine, and was sensiti ve to na loxone . These results indicate that part of the trimebutine- induced excitatory effect on motility in the canine small intestine is due to opiate receptor-mediated activmion of c ho line rgic nerves.

The atropine- insensitive component of the above described effect m;:iy he due to a d irect effect of rrimeburine on smooth muscle, to interactions with other nerves (cg, suppress ion of VIP release [22)) , or to the ability of rri mebutine to stimulate the release of morilin. When the small intestine was active (following local electrical field sti mulat io n) , trimebutine (0.) to 100 µ g) caused inhibition (33) (Figure I). The effec ts of trimebutine o n the canine stomach and small intestine re-

scmblc those obtai ned with met-enkephalin under rhe same experimental condi tions, and arc t hus likely mediatcJ byµ or o opiate receptors O '3,34 ).

T he actions of t nmebutine in the colon arc more complex. U nde r the cxperi men Lal cond itions described a hove, rrimcbutinc h,1d no excitaiory effect in the cani ne colon following clmc intrnnrtcrial injection. When the colon was act iva ted, tr imehuri ne caused cit.her weak inhibition or produced no effect at a ll (33 ). T his profile is si milar to that seen with the natura l opiates met- nr leu-enkcpha l in or dynorphin Lmdcr the sa me conditions. Inhibi t ion of colonic motility was most marked wi th dynorphin , sugges1ing that it i~ mediated primarily by K receptors (34). These findings raise the possibil ity th;n the excitatory actions of opiates ( inc luding

CAN J GASTROENTEROL VOL 5 No 5 SFPTFMRPR/CXTOBER 1991

trimehULine) on colonic function have their primary sires of ac tion outside the colonic wall.

PeriJ)heral i1ersus central actions uf rrimebutine. Studic~ in the dog suggest that the stimulatory effects of trimehuc111e are medi a ted v ia peripheral rather than central npiatc reccpwrs (35). The actions of trimehut1nc were blocked by intravenous but not intracerehroventm: ula r administration of naloxonc, anJ could not he reproduced following intraccrcbmvenm cu b1r injection of trimehutine ( 35 ).

Effem of trimebutine on the release of gut /Jeptides. le has been shown in the Jog that intravenous injection of Lri mebutine attenuates the pnstprandial release of several gut peptides (36). Trimebutinc (IO mg/kg/h) comple tely inhibited the increase in plasma gastrin, pancreatic polypepnde, imulin, gastric inhibitory pcpt idc and glucagnn. Since several of these peptide~ may influence motility, it 1s possihlc that some of the effects of trimchutine \ll1 postprandial motility arc due, m least in part, to alceratiom in plasma peptide concentrations. These effects ,1rc s1m ilar to those ohserved with lcu - and merenkephalin ( 19).

In contrast tn the inhibitory action of trimehutinc on the above de~cri bed peptides, trimebutine c wses an increase in the plasma cuncemrnt ion of motilin m the fed or fasted state (37). In the fasted stare, the admirnstration of morilin wa~ also associated with the Jcvelopmcm of a burst of propngmeJ contraction very similar to that seen wi[h phase 111 of the spontaneous migrat ing mntor complex. S ince the latter is also associated with increase~ in plasma mot ilin, i1 ha~ hcen suggested cha[ endogenous motilin induces the migrating motor complex (38). The subject 1s Clll1l rnvcrsial, and others claim that the 1rn,tilin rise is secondary to contractile act ivity in the intestine (39). Regardless of the cnusal rclarnmship between endogenous morilin and spontaneous migrating motor complexes, it is possihlc that morilm rnntrihutcs to the trimehut ine- induced motor responses int he dog, since the observed increase in motilm occurred just before the migrating mntor complex.

THE EFFECT OF TRIMEBUTINE ON

GASTROINTESTINAL MOTILITY IN HUMANS

Actions on esophagea l motility: In healthy fasted subjects, intravenous administration of trimehutine (50 mg) resulted in a 1wofold increase in lower esophagea l sphincter pressure recorded manomc1rically using the pull-through techn ique (40). The response lasred approximately I 3 mins and was compared tn saline injection in a single-blind study of 20 subjects. The effect of t r1mcbutinc on lowe r esophageal sph incter pressure is different from that of nHirphi nc whi ch, a t 111tra vcnous doses of 8 mg, decreased sph111cter pressure ( 41 ,42). Since morphine interacts with µ receptors, the trimehutinc action is li ke ly mediated via o receptllrs, which have been identified in the oprn,sum lower esophageal sphincter ( 4 3 ). Although the effects of t rimebutine on the esophagea I hody h,we not been described, ,1 met-enkeph,din analogue Jose -dependently increased the amplitude, duration and propagation vclocity of deglutition-induced contra crio ns in hunrnm (44). Taken together, these finding:, misc the possibility that trimcburine may he beneficicil in reducing gas t roesophagcal reflux. In an unumtrolled ~tudy, admini:,trat inn of rrimehutine elixir appeared to reduce ga:,trne,op hagea I reflu x in patients with endoscopicn lly proven csophagitb (45). Trimehuune reduced the number and total durntion of ac id reflux epiw de:, assessed by pl I mnnitoring during a > h pm,tprandial period in IO patients. The effccr of trimehutine OLLurred independently of rhe degn.:c of esophagn b. Effect on gastric motility and emptying: It is generally accepted that exogenou, opiates decrease gastric emptying in an ima b nnd in hum<111s (46). In the anesthetized dllg, all opiates, including trimehutine, failed Lo stimulate gastric or pyloric motor activity when admirnstered hy close intrn -a rterial inicction, hu t they uni versally inhibited motility induced hy clec trical field stimulation (33,34).

In keeping with these data is the l)hservation that trirnchutinc delays

CAN] GASlRl)LNTEROL V()L 5 No 5 Sr·l'Tl:Ml \l:.R/lx.Tl)lll ·(( 1991


gastric emptying 111 healthy human subJCCts, illustrated in a plaLehocontmlled, double-blind, crossover st udy (47). In tha1 study, orn l adm inistra tion of t rim ebut ine (200 mg) significantly reduced the gastric emptying of liquid by approximately 19'){,. Ciast ric emptying was measured 1 h after trimebutinc administra tion by a double sampling method using phenol red dye. The Olhet of action was 20 mins, and che maximum effect of trimebutinc was observed at 40 mins. The therapeutic value of th is effect iSt111clear, and it may even be detrimental in 1hc applicat ion of the drug to treat gastrocsnphagc:il reflux. Actions on small intestine: Sevna l studies have shown tha t 1rimehutinc affects intestinal motility in hoth 1he fasted and postprandial states (48,49). In the fa,ted stnte, intravenous administration of trimehutine ( 100 mg) induced ahornll y propagated motor complexes tha t resembled the intestimd component nf spontaneous phase Ill interdigesuvc migrating motor com, pl exes in terms nf duration, propagmion velocity and frequency of contrac tion (48). However, unlike sponrnncous migrating motor complexes thar occur first in rhe gast ric antrum, trimeblllineinduced complexes occurred only in the mtestinc, and antral activity was, in fact, suppressed. This effect of trimchutine was abolished by illl ravenous in fusion of naloxone ( 40 mg/kg/h), and was :,1mi lar to that induced by administra tion of morphine (49), indicaung the involvement of opiateµ receptors.

In anothe r study in which intr,1-venous trimehutine ( 100 mg) produLed .,imilar respnn:,e,, the phase Ill -like 111lllllr complexes differed from ~ponumeous rnigrat ing motor complexes 111 thar they were not acuimpanied hy an increase Ill plasma moti lin (50). Fur-1hcrmore, others showed that administration of trimcbut inc suppressed plasma morilin concentrations in fa,ted healthy subjects, .ind that thb effect was na loxone semit ive (48). These results differ from those reported in the dog, in which trimchu tm e-ind uced phase II I-like activ ity was accompanied hy an increase in pla.,ma mmilin concent rat ion (37). These findings reflect

189

OJI I INS AN() l);\Nll:I

> ... ::; §_ :to .. .J .. <( C _o 0 C,

z. <( > a::o A. .Q • .... "'• O• A. • .. z C, -.s Wat :--w a: (.)

~ NORMAL SUBJECTS

IBS PATIENTS

Figu re 2) T/1i> inacmc, 111 J1ost/mmdie1/ colonic moullly m 1/1e /1resence ur a/,1ence of rrimeh11tine 111

nomwl mhjec1s and 111 /)(Uient, w11h irriwlile bowel syndrmne. The incrccLSC in morili1y is ex/Jresscd m the mean percenwge of inne(L,r abo1'e fasting ,,e1/11es. Shown is the mean ancl SEM for each grouJJ, hmed on an analym oj eight nonnal suh1cct.s and seven />auents with mitahle bowel syndrome. Ue.1/mn.1e., following tTimch111ine admmistration are shown hy the hatched hars. The figure shows that 1rnnelmt111<! reduce~ the uhnomllll incrca,c in /mst/>l'a11cl1al nwwr ac1i11ity in irrirahlc /,owe/ syndrome /Ja11em1 h111 do£'s nut affect 11101<,r actil'ity in hr?ulthy controh (uclapted from reference 56)

~recie~ 1itfcrence~ in the control of intcrdige~rive motility hy oriatcs in an imals anJ humans.

In the fed state in humans, intravenous ad ministration of t rimebutine ( I 00 mg) 40 mins after a 500 kca l meal interrupted postprandial motor activity wirh a motor comrlex that resembled rhe migrating motor complex of the interdigestive state ( 50). The action of trirnehutine on postprandial in test inal m1)tility may reflect the abi lity of that drug to prevent rhe postprandial increase in the hormones gHstrin , insulin, gastric inhihi tory polypertide and glucagon, dcmonstrnted recently in the dog ( 36).

The ability of trimehur ine to stimulate propagated motor acriv it y would suggest that the drug may he useful in accelera ting transit through the small intestine. This was shown with the duodenal transit of liquid in heallhy suhjects using a dye di lution technique ( 51 ). The effect of I rimebutine nn small bowel transit may underlie it~ reported benefit in reduci ng duodenogastric alkaline reflu x. ln an open study, tri -

mebutine was shown to reduce episodic alka line reflux in patients with endoscopically proven bile reflux gastrit is (52). In this study, gas tric pH was monitored in 12 patients for 24 h before and after one nwnth of oral trimehutine 1herapy (6 mg/kg/day) . Trimebutine had no effect on gastric hasal pH but significantly reduced the mean numher and durm ion of episodes during which the gastric pH exceeded 4. This was associated with symptomatic improvement in eight of the [ 2 patients. Although the results were interpreted in light of an effect of trimebutine on gastroduodenal motility, the exrent 10

which the data were influenced by a direct effect on gastric ac iJ secretion is not known.

The stimulatory effect of trimehutine in the intestine has also been applied to twn conditions associated with s low t ransi1 in the sma ll bo wel : paralytic ileus and p ·eudo-obstruction. In patients with postop<'rative ileus, administration of intravenous rrimcbutine (50 to 300 mg) increased sriking activity in the small intestine, and dw

response was dose-dependent ( 5 3 ). lnf11sion of trimehutine for 12 h rer Jay was a !so reroncd !Cl a<..lekrnte the nn~ct nf the first passage of fl a1 us rostorcra-1 ivel y in these pmicnts, from a mean of 70 to 54 h .

In infants with pscudn-nbstrucunn, characterized manomct ricall) hy ex ten· sive d isrup1ion of interdigestive mmility in the sm,111 hmvel , intravenous t rimehutine (, mg/kg) induced phase Ill-like motor comrlcxes which were propagated .ibornlly ( 54 ). ln two of the four patients studied, the :idministrn· tion of trirnebutine was accompanied by the passage ol flatus and a reduction in abdominal gir1 h. Actions on the colon: Recrmigmo1d motility in normal s11hjec1s. In fasted ( 48) or fed (55) healthy hum;in subjects, neither intravenous nnr nrnl administration of trimehut ine ( l 00 mg) had ,m effect on moto r activity measu red manometrically in the sigmoid colon; this is in keeping with the actions of naturally occurring enkephalins in rhe dog ( 56). These fi ndings again il lustrate that trimehutine differs from other syntheti c op iates sul h as mnrphin c, codeine and lorernmide, which 111-

variably .~ timulate mornr responses m the reccosigmnid (57,58). Because of regional differences, it should he cmp ha s i zed tha 1 resulis ohtaineJ rnanometrically in the sigmoid colun may n ot necessari ly reflec1 those recorded from mnre proximal regions nf the colon. However, the ahsencc of a rrirnebut inc effec t elsewhere in the healthy colon is support ed by rL'rons of unaltered colonic trnnsit times fo llowing trimehutine administration in subjects with 'normal' colonic transit (59).

RectO$igmoicl motility 111 /Jatient~ wirh inicable bowel syndrome. In a study of irrirnh lc howe l synd rome patients, motor activity wa~ recorded manometrica lly heforl' and after a meal (990 10 1100 kca l) ;md then for 30 min~ after the adm inistrati on 11f imravcnou, trimebutinc ( 50 mg) (60). En1ry cri1eria included dcmnnstrntinn of an 'ahnormal' colonic motor respome to a meal, hascd on the authors' prior experience with 20 normal ~uhjects. Of 16 irri rnhle howcl ~yndrtlme rmients entered, seven

190 CAN J <..,ASTRt1l'NTEJtt)J Vl)I 5 Nl) 5 SI l'TEMJll'R/<..x ,nfll R 1991

were classified as ex hihiLing 'hypomocility' wiLh a poor response Lo meals, and seven were classified into a 'hypcrmotility' group exhibiting an exaggcraLed meal rc~ponse. In irritable bowel syndrome patients with basal 'hypomotil ity', trimehutine significantly i11creascd Lhe postprandial motor response, whereas in the paLicnb witl1 basal anJ postprandial 'hypermmility', trimehut inc ~ignific ,rn Lly reduced motor a<.:Livity.

The suggestion o( a modulating effect of trimebutine on colonic motor activity was further supported by a recent placebo controlled, crossover study in which rccrosigmoid motility was recorded m,momcLriGdly in nine constipated irriwblc bowel syndrome patiems and l l normal subjects (55). Trimebutine was ,1dminiSLcrcJ in a single oral 200 mg dose 20 mins before the ingestion of a mea l. Following placebo ingestion, the rcctosigmoid motor response to the meal (gastrocolic reflex) w<1s sign ificantly larger in the irritable bowel syndrome group compared to cunt mis ( increases over baseli ne o f 49.1 % versus 2 l .9'Y.,). Adm111istrntion o( trimcbutine attenuated the meal-induced respnn~e in the irritable bowel syndrome group (re<lucing it from 49.1 to 28.9'Xi), bringing it into a range closer to that w normals (Figure 2). In contrasL, Lhe opposite trend wa~ ohscrved in normal subjects in whom trimebutine caused a

small, statistically in~ignificant increase in the postprandial response (from 21.9 to 23.9%). S ince this was an acute study, symptoms were not assessed. Trans it studies: In const ipated irritable lx1wel syndrome paLients, oral administration of trimcbutinc (200 mg Lid) for eigl1L weeks significantly improved ahdominal pain and constiparion, superior LO pla cebo in a double -blind crossover study ( 3). These findings were accompanied by a significant decrease in whole gut transit time of radiopaquc marker&. Since the colon is a major determ in,1nt of gut Lrnnsit, these stud 1es suggei;r an effect o( trimcbutin c nn colonic mot ii ity in constipated irritable bowel syndrome patients.

Similar results were obta ined in another double-blind, placebo control-

led, crossover sLudy in which irrirnble bowel sy ndrome paticnLs will, abdominal distension, pain and consLipation were given Lrimebutine or placebo for one month, and each treatment was separated by a one week washout period (59). The study group contained 12 patient~ wiLh slow colonic transit, and 12 pmiems with normal Lransit times of bs Lhan 40 h, assessed by the passnge o( ra<liopaquc marker~. A II patients had failed to improve on fibre supplemems prior to entering the study. Trimcbutine therapy caused a significant reduction in colonic trnmit Lime from 105±[9 to 60±11 h (P<0.015) in rhc slow transit group, without a significant change uccurring in the group with normal colonic Lransit times. Symptoms of abdominal distemion and pam relieved by dcfccaLion were significantly improved in both groups, huL there was nn change in stool frequency compared LO

placebo. Colonic myoelectrical activity: The field of recording and imerpreting myoelectrical signals from Lhc human colon in vivo b fraught wiLh difficulLies and conflict ingdaw. There 1s agreement hcLwecn some groups that myoclectrical activity may he described in Lerms of long and short spikt· bursts (61 ). Shon srike hursts last about 3 s, arc lncnlizcd. seldom propagate, and arc common in the proximal colon. They serve Io

retard Lhc fecal stream and prolong Lrnnsi t; they arc found in increased numbers in consLipaLed humans (62) and experimentally constipated dogs (6 3 ). Long spike hursts last abllllL 2 l s, may propagate ,id- nr aborally, and arc found mainly in the disrn l colon (62).

Pl,1ccbo com rolled st udics on Lhc a er ion of Lrimehutinc \)11 colonic myoelectrical activity in irritable howel syndrome paLients have yielded cnnflict ing results. In one study, trimebutine had nu effect on shLirt spike bursts in eid1cr constipated i rriLablc bowel syndrome patients nor in those with diarrhea (64); trimebutine <lid reduce the duration nflnn.g spike hursts in both subgroups of patient s, but the therapeutic significance of this find ing i~ not apparent. However, in another study ( 59), trimebutine significantly in creased the number of propagated spike

CAN J GASTRl )ENHROL VL)l 5 N() 5 SEPTEMBloR/0CTOlWR 1991


hursLs in pmicms with const ipatinn. Since Lhis type ot activity has hcen posiu vcly Cl1rn:lated with propubivc movement in the colon, the Cinding 1s in keeping with the documented effects of Lrimebutinc in accelerating colonic Lrnnsit in irritabl e bowel syndrome paLiems witl1 rnmtipat 10n (>, 59).

In an uncontrolled study nt the action of trimcburine on rectosigmoid activity in normal subjects and 1rriLahlc bowel syndrome patients, trimchuune appeared w exhibiL a 'normalizing' dfcct (65). Recordings were wken from

rhc region of the recrosigmnid junction where the authors claimed thnt spiking activity remains relatively cnnsrnnt at a frequency n(O LO 2 spike hursts/min. In five nor ma I subj ecb, i nL ra vcm>us tnmehutmc ( lOO mg) had no :.uhstanLial effect nn elcctricnl acLiviLy, hut s t imulnLed spike bursts in o ne asymptlll11atic subject who had no discern ible basal activiLy. ln seven irritahle howcl syndn)me paLienLs with in<..rcascd basal sp iking activity, LrimchuLine .ippeared tn dec re,1se acLivity. An addiLinnal 11 irritable howcl syndrome pauenb had normal hasal spiking activity, and in e ight of these, trimchutme had no effect but the drug incr<..·ased spike bursts in the remaining three paucms. Since no information was provided regarding d,e clinical sL.i tus ,if Lhe trimehut inc rcsp,mders and nt1nrespt1ndcrs, and ht:causc the study w<1s uncontrolled, the dau1 arc n(

l11n1ted use, although they may provide an example n( .i bivalcnL or 'normal-1: ing' effect of trimchuLine on human gastrrnntesrin,11 mntility. Synthesis: In halancc, the results of studies un colonic transit, motility and myoelcctrical activiLy are consistent wi th the ,·,ew that trimehuLinc accclermcs slow transi t in Lhe colon by en couraging propagared motili ty in the proximal colon and reduc ing nonpni· pagated activi ty in the sigmoid region. The clinical extrapolation of these daw is Lhat trimchuune may be u~eful in treating constipation due LO cdonic inertia.

REFERENCES I. Walter~ JM, Crean P, McCarthy CF.

Trimcbuunc," nc,, ,11111,pasmod1 <.. in the treatment nf <lyspcpsi.1. ln~h Med J 1973; I 0: 380-1.

191

l \ )LLJNS ,\NP [).\NII I

2. LullL'l ke K. A tnal 1if tnmehuunc in , paMic colon. J Int ML·d Re, t 978;6:86-H.

1. Mo,hal MG, I lermn M A tl111 1L al tn,d nf tnmchuum• (Mehut 111 ) in spa,t1c colon. J ln r Med Re, 1979;7:2 n 1-4.

4. Pa,ciuJ X. Fnm,m F, Petnux I·, Vauche D,Jun1enJL. AcrionJe la 1ri1nc5huum· ,ur 1.i mntnu t,' )(,1'tro- 111t e,r111ak·. Ga,t roenr,·rnl ( ' I 111 B1<1l 1987; 1 I :77H-8 1 B.

5. Roman F, Pa,c1ud X. Taylnr JF. Jun ien JL. lnt er,1ct1<H1' of mnwhurmL' w1rh guinea pig op11>1d receptor,. J Phann Phamiarnl I 987;,9:404-7.

6 Pascaud-X, Rnman-F, PL·t11ux-F. Vauche-1\ Ju111en-J-L. lnvolvenwnt of op,atl' rcceptm, 111 the modl' of .,uinn of trnnehuu1w. G,1, tn11:nteml ( ' Im Biol 1987; 1 l :77B-H tR.

7. I lughL·, J, Smith T W. K, hterl,t: I lW, Fotl1L•rg1I I L, Mnrgan BA. Morn, I IR. ldl'nl il1c.l!Hlll llf rw11 reh1t l'd pentapl'ptide., from till· hrain \I'll h potL'nt ,1p1arl' .,g,111"1 ,1u 1,· 11 y. Narurl' t 975;258:577-9.

H. Lord JAi I, W.ttL·rfi eld AA, I lughe, J. K1hterl1r: I IW l:.ndllgl·nou, op101d pcpt 1dc,: Muluplc agorrn,ts and rl'ccptor, . Nature 1977;267:49'i 9.

9. SunJlcr F, BJ,trrc ll A, l\mclwrl,, EkhlaJ E, I labn,on R. Localiza t 1<111 of cnkephal in, :md 1>t her cndogen<1u, op101d, 111 thl· d,gc,u n: tr,IC t.

Gasrrrn:nterol C lm Rini 1987;11: l4B-26B.

10. Lu,,nn LI. Sten,,gaard-Pedcr...111 K. lmmunocytochenm:al and ultras! 1 ucturnl different iat H m he1 ween met-L·nh·ph,1lin. lcu-L'llkephal111 .111d mcr/ku enkephalin 11nmunme,Kt l\'L' neurons of fclml' gut. J Ncur<N:i 1982;2:86 t -7tl

11 Costa M, FumL·,, JB, Cuello Al. Scpm:11,· popul:11i,H1s nf npioiJ u mta111mg neurone, 111 the gu111l'a

pig mtl'st !Ill' Neuropl'pt1de, I 985;5:445-8.

12. Co,ta M, Fume" JR, U 1hbom IL, Murphy R. (. 'hemK,11 codmg an,I proj ,·ct ion:, of op101d pl·pridl' cont .11ning 11<.'umns 111 the gu11w,1 pig mte, t inc. Neurosu LL'tl 1985;22:SI 9-55.

11. Rurb T F, G ,lltg:m JJ . I liming LI ). Porrl'l,1 F. Bra 111 , , p111al 1:t>rd and pcnpllt.'ral , it l's of acrum of enkcphaltm and t1t hl' r end,1gL·nou, op101d, on ga,t rnmt e,t m,il mot ii II y. G ast menrernl ( '1 m R,ol 1987; 11 :44B-5 I B.

14. Stl'Wart JJ, Wl·ishrodt NW, Burb T F CL·n1 r.1lly mcd1.11ed 1ntl'stmal , t imul:lt 1on hy nmrph,nL'. J Ph,mnauil Exp Ther 1977;202: 174-8 1.

15. Stewart JJ . Wmhrodt NW, Burb H ·. Cc111 ral and 1wnphl·r:tl au ion, of m,irphme 1111 mt L',tmal tran, 11

192

.I Pharmarnl Exp T her 1978;205:547-55.

16. l'orrcc.1 F. Filla A. Burks TF. The ,pmal cord-mediated opi,1te effect, <111 gastro111tL·srinal I ransicnl mice. J Pharmacol Exp T hcr 198,;227:22-7.

17. Filecc1a R, Jule Y. Effect-of enkcphalins on synaptic transmiss inn 111 the inferior me,L·nrenc ganglion nf rhe cm. J Phys1ol ( LonJ) 1983: 345-66.

18. Bitar KN, Makhlnuf G L. Selec tive prc,cnn· of op1atl' receptors on 111testm.1l urcuLir muscle cells. Life Sci 1985;37: 1545-50.

L9. Champmn MC.Sulliv,m SN, Blnom SR. Adrian TE. C hristof1dl·, NS. The l'ffects n( naloxone ;ind morphine on pn,tpr,mdinl ga,tromtest111al hormone ,ecrcuon. Am J Ch,tmentnol 1982; 77:6 17 -20.

20 Pmtra, P. Moril111 1s a d,ge, uvc hmmonL' 111 the dog. Gastn11:nterology t 984;87:909- 1 3.

21. Fox JET, Da111cl EE. Exogenous opiates: T heir loc,11 mel han,sm, of ,1ct1on 111 rhe canme small 1ntcstim· and stomach. Am J Phy,iol t 987;251:C t 79-88.

22. Manaka 11, Manaka Y, Ko,tolanska F, Fox JET , Daniel EE. Relc.,,e of Vt P and suhswncl' P from 1s11Lircd pcrfll',ed canine ileum. Am J Physml t 989;257:G 182-90.

2 ~ l~.irrett JM, Sauer WG, M<1ertcl CG. Cnlon il mot ility 111 ulcerarivc coltris after opiate adm mist ration. O,i-tn11:nterology 1967;51:91- 100.

24. Dvomk AM, Connell AR, D1ckers111 UR. Crohn's disease, a .,canning decrmn m1cro,cnpic sruJy I !um l\ uhol 1979;!0: 165-77.

25. Bishnp AE, Polack JM , Bryant M<.,, Rlnom SR, I l.11111hon S. Abnorm,1li t1es of v,1so;Kt1 vc intl'st ma! polypcpttdl' containing nerves in Cmhn's disease. Ca,troent erology 1980;79:85 3.

26. 1 larwy RF, Read AE. Effl·,t of cholecyswkinin on colonk motility .md symprnms 111 p,ment, with 1mt,1hle bowel syndrome. Lancet I 973;i: 1-) .

27. Waller S, M1siC\\1cz JJ , Kiley N. Effec t of ear111g l lll nmulity of the pelvic colon in const1 p:1t 1<m ,rnd 111 di;irrhoea. Uur 1972; 13:805- 1 t.

28. Sun EA, Snape WJ , Cohen S, Rl·nny A. The role nf opiate rl'ccptors and d 1ol111erg1c neurons 111 rht g.1smx:olic re,pome. Ciastn x:n1 emlogy I 982;82:689-9 3.

29. Buen1> L, F1ora111onri J . Enkeph,il111 ,, other endogenous opioid, ,md colo111c mori l,ty 111 dog and man. (~m,tml'nlerol Cl m B,ol 1987; 11 :69R-76R.

10. h ora111ont1 J, Farge,i., MJ , Bueno L. Comparative cffeu s 1i morphine and <..ydazounc on ga,tmintest 111al motility 111 u m,c1ous dog. Arch Int

Pharmacodyn T her 1984;270: 141-50. 11 . Schulz R, Wu,rcr M, I k rz W.

Centra lly and penplwr,,lly llll'd1.1tcd 111h1h1t1on of 111te,t1n.il mou lity hy op1oids. Neunyn,Schmeihd,,·rg Arch Ph.umarnl !979;108,Z'i5-64

32. Jule Y. Effl·I, de L1 tnmt.'huunL' ,ur la rr;111, m i,,ion c.:hol inerg14ul' .1<1 n I vc.iu dL'' neurones du ganglinn llll'SL'l1(Cnqu, 1nft.'neur du L1 p111. ( 1,Nrnentn,11 Cl111 Biol 1987; l l:8H\-51~.

D. L),1111cl EE, l..::1htolan,ka F. h,x IET L1x.,,I act ion, of 1r1111l'hut111L· ,m c.1111nl' g.1st mint est mal trau. ( ,a, tn>L·ntcrol Cl m Riol 1%7;l l :86B HB.

34. Darnel EE. fox JET. Alles1:hL·r 11-l). Ahmad S. Kmtol:111, k:1 F. 1\•nphcral action, of op,.,cc, Ill l,111tne g,1,tm1111e,t 111,1I tr.Kt: Au11111,on ne rves and mu,ck,. (. hst rnen1 nol ( '1111 R,ol 1987;1 l 1'iR--I \H

,5. h or;imonu J. hirg1•a, MJ, !111L·11<1 L. Thl· involvenw111 ,1f np1;1t l' rlTl'J'l11r, 111

t hL' effects of tnnwhurme on 1111e,t 111,,I 111ot1!1ry 111 the consc 111u, Jog. J Phann Ph;1rmacol t 984: 16:6 18-2 I .

16. Pn11ra, P, I l111Je C. l,oyL"r R. J11n1u1 JI , Pa,c1ud X. Grcl·nherg (,R Eftct de la tn m<:hut till' ,ur la l, hera t u,n plasm:nique pl1s1-p1 and1,1k• d'hormnnl'' gastn 1-111re,1111,,le, d ie: le d11L·n G.istrt1enten1I Clin R1,1I t987;l l:94B 6R.

17. Po11r:1s P, I lnnde C, I l.l\ :,111ko\a I, L'I :i i. Effec.:t, of trnnehutine on 1nt e,11 nal nu1t il1t} ;1nd pl.1s111;1 mo11l 111 111 Jog. Am J Phy,1nl 1986;25 I :c.i 349-5 3.

38. Pn11 ra, r. Trudel I . Con, nik par I.-, opt.Ke, endngt·ne, ,k l;1 mnt ii 111cm ll ct du Lomple, moreur m1gra111 l Ill': k ch 1cn. Ga,trnenren1l l ' l111 B,ol t987;l l :621'\4B.

39. Sarn,1 S, Chl'Y WY. London RI:, Dix.Id, WJ. Myer, r. ( ' hang T M. Cw,l·-aml dfl'll rd.11 1011,h,p hcmel'n nm11 l1 n and m1gra 11 ng myol'lell nc complexes. /\m J Phy,ml t 981;245:l,277-84.

40. &·I A. R1rnrd J-L. !\·net A, Noun K. Tlw aC llt>n ,if mtravenuu, 1n ml·hut11w on the lt1\\ l'r L''l 1ph.tgl'.il ,ph , l1l tL'r ol till' e,ophagu, of the heal! hy adulr. l , m Med France l 982;89:2954-7.

41 . I tall AW, Moo,a AR. Ch,rk J, Coolq (~R. Skmner l'lB. T he effeu, ,if prl'll tl'd1ca11011 on thl' lower L'soph;igeal high prcssu rL' :nnl' and reflu, ,taru, of Rhl•,u, monkl'y, and man. ( ,ur t975;16: H 7-52.

42. Mmal RK, h;111k 1::B. l.,111gl' RC, Mc.:C11lum RW.1::fku,of 111orph11w and naloxl>l1l' 1111 e,nphage,d moul 11 y and ga,tnL empty111g 111 111.111 I )1g Dis Su t 98(d t :916-42.

4 , . Rau an S, tJt1ya l Rt..::. lde11 11f1c,1rion ,ind local 1:at 1011 of op1rnd rL'll'ptor, 111 thl· opo,,.,um lower l'st1phage,1I

C\N J C,\STROENTIRl )I Vnl 5 Nn 5 Si l'TI ~ll\lH./01.''Ttll\l R 1991


,ph111uer. J l'h.1rmacol f ,p Thl-r 111test111,il motil11, 111 n11rm,1l hum,111' h, I, ,peram ,dl' 1n d1 ,g,. ( )1g ( )1, sl I 1983;224:391 7. (. ,a,trnc111,·rnl C:lin Billi 1987;62:64 I (l.

44. Stadwr (,, lhu1·r P, S11·111r111gl'r 11. 1987;1 l :97R-1101\. 58. Ingram DM, (. '..11d1polc BN. Hkl:i- of &hm1l'rt· U, Lmgcr B, W1nkkhnl'r S. 51 St hang J( ', Mulkr J, Rim I, (.,rt·111l'r ,1p1.1ll'' 1,n ga,1n >1.l11<1<knal 1111,1 1l1t ) Dmc related l'fkn, pf the synthl't K J F. Efkt , .1ccclcr:11l'ur, de l)chrid:ll fo llllwing , 111 gic:il npcr:nmn. ()ig 1)1, Inl't•enkcph.11111 ,malllgul' FK l 3-824 (trnnehutmd ,ur k rrnn"t du!ldcn.11. St, (981;26:989-92. nn l''<lphagcal 11111td11v 111 heald11 J Ml'd Stra,hnurg 1977;8: 115-8. 59. ~ hang JC, ()l'\ rnl'dl· ( ,, P1lntl' M hum.ins. <.,a,tn>l'11l l'r<1h1gy 52. (,l1km.111a, M, Sn111ll,K P, (,,1tml'at1· Rc.:11d1cml dfru, of 11 imc.:hu111w 111

1982;tH:1057 6 1 S,1illa111 (,, Prat It Effct ,ur k rdlux p,1t1ent, ,ufknng from 1mr.1hk h,ml'i 45 Gn"el 111 A. Efku of L khn,l,11 011 ,l111>1.lcn<1 ga,tn>cpc de C,1 mndif1Ca11nn d1,l'.1,e (IBS) w1rh norm,1l 1ram11 nr

g~,m1c,oph,1gt·al reflux :1s 111l',lsurcd h) ,I,• l.1 motnl 11c d11(1dcnal 1ndu1t1' par la c,m,t 1pat i, 111. ( ,:1,1 n ll'llt<.:rnlogy prolnng<.:d pl I metry. <. ,:1: t-.frd Fr:incc rrimchu1111e. Actual ire, Tlwr M( ' J) I 988;94:A40 3 19hZ;89,1Z. I %4; I 3:65 3-o. 60. Meunier I', L.1mh,.:rt R. Efkts dl' l,1

46 Duhrn, A. En,IPgl·nou, op1111d,, g,1st nL 5 \. <.,rl'nll'r J F. Sch.mg J·C, l\1uLhl'I J. trnnchurml' ,ur la motnLIIC u1lique m,lt1l11), and ga,tm: empl ymg. Ftude l'icLtn,myograplrn· .il', effc.:ts ,k Jans le, colopatlrn:,. (,:1,1 roL'ntl'rol Ga,tn>t·ntL·r,,I ( '!in R1ol la t nml'hunnc ,ur la motnl Ill' C lm R1011980;4:Z61A. (Ah,1) 1987;1 l :56B-6 rn 1111e,tinal au cnur, dl' la p(·node p11,1 61. Bueno L, F11>ramnnt1 J, Rulh·h11,L11 Y.

47. Suyama T, M1yo,h1 A, I 1(1n R. npcracoirl' J Ml'd St ra,h(lurg Frc.:\1110, J, Coul<>n P. Fvaluat lllll of I,h1111<>t1> M. 's111d1c, on lhl' d 1111l ,li 19775: 1 Vi -8 colo111L 111)'<ll'kd rt Lal ,K tl\'ll y 111 cffeu, of tnnll'hutme (TM906) on 54. Brnge N, C.irg1ll <.,, Ma,h,1k<l L, l 'nard hl',dth and hmctllln.il di,ordl'r,. ga,tnc l' lllpt ying 11ml' 1is111g d(luhlc.: JI\ Nav,irmJ. Trnnl'hutm<.: 111duLed Uut 1979;2 I :480-5. '><lll1J'I mg llll't ho,! Jpn I\ rd1 I 111 nn ph,1,l' 1111,ke ,1Ct1\1ty 111111fam, \\llh 62. BuL·no L, h or,tm,11111 J. P.llto.:rn, of Mc.:d 1980;27: I 59-6 7 111tc·,r111al J11(1td1t) d1.,onlc.:r,. J PL·,li,11 r u1lo111L mo1il 11y. Cl 111 Rl', Rl'I'

48. V~lor1 R, Shann11n S, RL·dd) N, l),1111L'I (1.1stf1lenll'l'Ol (987;6:548 51 1981; 1:91- 100. EE, C.,1111" SM Tho.: ,ll r,,m nf 55. Shannon S, f h,llmg,ll'llrth J, Cook IJ, 61 hor:imonu J, Uaru.1,V11lr R, Bueno I , mm<.:h111111l' 111,1k·,1t<.: rn, l'ollm, SM. Effeu of tr1md1u1111e 011 Rtllh·hu,ch Y. Colome: myo1:lcctm:al ga,tm111tr,11n:1l moul11y "ml'd1,1tc,I hy postpr,11hlt.1l colrn11l mo1or act 11·11 y 111 ,Kt1Vity and propul,ion in the.: dog. opiate receptor, 111 human ,uhJl'll,. hc.:,1lth\ ,uh1eu, and p.1110.:111, with [)1gDi,Sc11980;25:64 1. Ga,tmcmcml C lm B1,1l 1mtahk htmcl ,yndmml' 64. hc.:,1110, J, hmamrn1t1 J, Rul'no L. 1987;! l:102B4B I C,:1,1mL·111l·rol Mo1d11y 1989; 1:9-14. f:.ffl·c1, uf t nml·hutinc.: on u1lonit

49 W.11c.:rf.11l Wr Ek·ctnlal p:ml·nis 111 56. Bueno 1. r 1or.1m<lnt1 J, I l11nde C, 1111·,,clectm.,1l ,1ctiv1ty m 1mt.1hle howl'i thl' human 1e1u11um w11h anJ w11hou1 F.1ragca, MJ, Prnn1 MP. C \·n tral and ,yndroml' pat 1c·n1,. l::ur J C lin vagowmy: M ,gr.it 111g my<>cku nrn l Jll'fl phc.:ra I cont n ,I of ga,t rrnntl'St I n,d l'h.irm,tcol 1985;28: 18 1-5. o>mplcxc, ,mJ the 111flt1l' llll' of .111,I colPll ll mill ii 111 h) l'nd, >gem ,u, 65 !,man 11. l.111><1 B. Nak.K he R. Effcu of morph me. Surgl'f) 19h 1;94: I ~6.9. op1.1te, 111 n,n,uou, dog.,. 'I \·hndat · ( t rnnehurmc.:) on ,1gmoid

50. Chatiss.1de :->, ( ;rand1ou.111 S, C, ,11111r1c.:r <. ;,,, t rol· n11·n,l11g1 I 98'i;H8:549 5(1 and rl'ctn,1gm111d mu1 d11y in normal D, T h1rnm11 l)uft.111d I), I lrnr, II;. 57. hor,1mn11t1 J, F.trgl·a, MJ, Bucn(1 I and p.11hol<1g1<.:a l , tatl'' G.i.: ML•d Effo:u of trnnd,ut 11\l' on prox1m.1I ,m,111 St 1mu L111on of ga,rn ,mtl'st 111.d 11101 ii 11 ) Fr,mll' 1981;89.1272 6

CAN J (,t\STRtll !'-.Tl Rlll Vil! 5 N11 5 S I l'TI ~1111 H/On1 lBU\ ( 991 191

Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

Documents

gastrointestinal motility and