Morphine and Gastroduodenal Motility - Springer Link

Digestive Diseases and Sciences, Vol. 44, No. 11 (November 1999), pp. 2178 ± 2186

Morphine and Gastroduodenal Motility TERENCE D. LEWIS, MB, BS, FRACP, FRCPC, FACP

This study inve stigate d the effe cts of intrave nous morphine on gastric antral and duode nal motility in healthy volunte e rs. Intrave nous morphine (both infusion and bolus) increased duode nal motility, typically as bursts of contractions similar to phase III of the migrating motor comple x. Intrave nous infusion of morphine 40 m g/kg/hr rapidly incre ase d duode nal motility in nine of 10 subje cts; in eight it was phase III-like . Intrave nous infusion of naloxone (40 m g/kg/hr) blocke d this e ffect of morphine infusion in ® ve of six subje cts. Morphine bolus inje ction (5± 20 m g/kg) in six subje cts (30 ± 42 min following a spontane ous phase III) induce d furthe r duode nal phase III-like activity; also, morphine bolus inje ction (5± 20 m g/kg) in ® ve subje cts (30 ± 42 min following a liquid meal) induce d duode nal phase III-like activity. Atropine (10 m g/kg intrave nously) was able to pre ve nt the action of morphine (both intrave nous infusion and intrave nous bolus inje ction) in inducing this phase III-like activity. The se obse rvations show: (1) morphine in ve ry low dose is able to stimulate maximal duode nal contractility; (2) the motility response is typically phase III-like ; and (3) morphine acts on opioid re ceptors to initiate this phase III-like activity, with the effe ct blocke d by antimuscarini c drugs. KEY WORDS: human; motility; antrum; duodenum; morphine ; opiates; migrating motor comple x.

During fasting, re curring bursts of maxim al contractility (known as phase III of the migrating motor complex, or MMC) propagate throughout the human small inte stine (1± 3). The se phase III complexes typically comme nce in the duode num, ofte n with a pre ceding gastric compone nt of maximum contractility. The maxim al duode nal activity of phase III is pre cede d by inte rmittent duode nal contractility (phase II) and followe d by a pe riod of duode nal inactivity (phase I). Fe eding produce s the typical fed patte rn, with abse nce of phase III activity for a prolonge d pe riod (3, 4). Sarna has propose d the pre sence of a ne ural network wholly within the inte stine controlling the ocManuscript re ceive d July 6, 1995; re vised manuscript re ce ived April 29, 1999; accepte d May 14, 1999. From the Division of Gastroe nterology, Jerry L. Pettis Me morial V ete rans Medical Ce nter, Loma Linda, California; and Loma Linda University Me dical Center, Loma Linda, California. Support for this study was provide d by the U.S. V eterans Administration and Loma Linda Unive rsity Physicians Me dical Group. Address for reprint re quests: Dr. Terence D. Lewis, Se ction of Gastroe nterology, Loma Linda Unive rsity Me dical Center, Loma Linda, California 92354.

2178

curre nce of phase III activity (5); the stimulation of this ne ural ne twork would e xplain the re porte d action of many substance s in initiating pre mature phase III activity. The factors inducing the de ve lopme nt of phase III activity in the uppe r gastrointe stinal tract (stomach and duode num) appe ar to be diffe rent from factors re sponsible for its propagation in the more distal small bowel. While the re is interspe cie s variability, initiation of phase III activity in the uppe r gastrointe stinal tract has bee n re porte d to be induce d by intrave nous motilin (6, 7), morphine (8 ± 11) , pancreatic polype ptide (12) , histamine (13) , metoclopramide (14) , and erythromycin (15, 16) , as well as intraduode nal infusion eithe r of alkali (dog) (17) or acid (human) (2). Morphine has be en reporte d to induce duode nal phase III activity in dogs both during fasting and afte r fe eding (8, 9, 18) , as well as in humans during fasting (10, 11) . Howeve r, studie s on the effects of morphine on human small bowel motility are limite d, as most have bee n pe rforme d in the postope rative pe riod (10, 11) , which may not be re pre sentative of re sponse s during health. The action of Digestive Diseases and Sciences, Vol. 44, No. 11 (Novem ber 1999)

0163-2116/99/1100-2178$16.00/0 Ñ

1999 Plenum Publishing Corporation

MORPHINE AND GASTRODUO DENAL MOTILITY

morphine may be to mimic the effe cts of e ndoge nous opioids (met- and le u-e nkephalin) , which are pre sent in the intrinsic nerve s of the myenteric plexus (19, 20) ; it has be en propose d that these e ndoge nous opioids may mediate inte stinal contractility (21) . The aim of this study was to measure the effects of intrave nous morphine on contractility of the human stomach and duode num (e specially its ability to initiate duode nal phase III activity) , in normal humans not re covering from surge ry, and de te rmine the e ffe cts of naloxone and atropine on the motility re sponse to intrave nous morphine . MATERIALS AND METHODS Healthy voluntee rs, free of gastrointestinal symptoms and with no history of gastrointestinal surgery, gave informed consent to the se studies. The study plan was approved by the institutional review boards (IRB) of Loma Linda University and the Jerry L. Pettis Memorial V ete rans Medical Ce nter. All studies commenced following a fast of at least 6 hr. E ach subject swallowed an eight-lumen recording tube, with e ight perfused side holes at 5-cm intervals from the distal e nd. Fluoroscopic positioning of the tubes was not possible as IRB approval was not give n for ¯ uoroscopy in normal volunteers. The recording catheter was positioned with its tip in stomach, and then advance d until it appeare d to enter duodenum (by noting the presence of duodenal contractions); if it did not registe r duodenal contractions, the n the cathe ter was partially withdrawn and again advance d. Position of the distal recording ports within duodenum was con® rmed by noting the presence of recurring contractions occurring at a maximum repetitive rate e qual to 11± 12/min on seve ral occasions. At least three ports had to register duodenal contractions during the study; if not, the study was discarded and, if possible, repeate d. The pressures we re recorded by Beckman, Statham, or Medex transducers, with permanent recording by a Beckman R611 Dynograph or Syne ctics PC Polygraph HR recorder with Syne ctics Liberty Medical Program, Polygram V ersion 5.06C4. Each lumen was perfused at 15 psi with distilled wate r by an Arndorfer infusion pump, at a ¯ ow of 0.4 ± 0.5 ml/min. All studies we re performed with the subjects supine. Repeat studies we re performed on separate days, at least ® ve days apart. Part A: Mor ph ine vs Salin e In fu sion . Ten male subjects (age range 22± 30 ye ars, 77.0 6 6.8 kg) were studied. Fasting motility was recorded for 30 min [initially chosen because the absolute refractory period for phase III in humans is of the order of 30 min (2)] before any infusions were begun. Then 0.9% saline solution was infused, with or without morphine, in random order, at 0.4 ml/min, for 90 min following the 30 min basal recording. Six received saline ® rst and four morphine ® rst. The morphine dose infused was 40 m g/kg/hr. The subjects were blinded to the order of infusion, and the records we re coded for late r analysis. Part B: Morp hine vs Morp h ine Plus Naloxon e Infu sion . Six of the subjects from part A participated in a study of infusion of morphine, 40 m g/kg/hr, plus naloxone, 40 m g/kg/ Digestive Diseases and Sciences, Vol. 44, No. 11 (November 1999)

hr, infused at 0.4 ml/min afte r 30 min of recording of fasting motility. These six subjects had all responded to morphine infusion with maximal activity in all duodenal leads within a few minutes. Because the maximal response to morphine was noted to occur within the ® rst few minutes, this study was truncated at 60 min, and the results were compared with the ® rst 60 min of morphine infusion. Part C: Low-Dose Bolus Morp hine Injection Followin g Spon tan eou s Phase III. Six subjects (® ve men, one woman, age range 22± 36 years, 66.8 6 11.3 kg) were studied. Fasting motility was recorded until a spontaneous phase III was observed in the duodenum. Thirty minutes following the onset of this phase III, morphine was injecte d intrave nously as a bolus in successive doses of 5, 5, and 10 m g/kg at 6-min intervals or until phase III-like activity was recorded. Part D: Low-Dose Bolus Morph ine Injection Du ring Fed State. Six subjects (® ve men, one woman, all from part C) were studied. Fasting motility was observe d for at least 30 min, and the n e ach subject drank 236 ml of Ensure (Ross Laboratories: ® ve subjects with the formula: protein 8.8 g, fat 8.8 g, carbohydrate 24.3 g, osmolality 450 mosm/kg; one subject with the formula: protein 8.8 g, fat 6.1 g, carbohydrate 40 g, as the previous formula had bee n withdrawn from the market and was no longer available). Thirty minute s following this meal, morphine was injected intravenously as a bolus, in successive doses of 5, 5, and 10 m g/kg at 6-min intervals (or until phase III was recorded). The occurrence of phase III activity during this period following the liquid me al was compared to the occurrence of phase III activity in the hour following a liquid me al in six comparable subjects (give n the same liquid me al as the original ® ve subjects), who were observed without intravenous infusion. Part E (a). Part A was repeate d in six subjects, who had responded to morphine with deve lopment of maximal duodenal contractility. Atropine (10 m g/kg) was injected intrave nously 5 min before morphine infusion was begun, with motility subsequently recorded for 1 hr during morphine infusion, 40 m g/kg/hr. The response to morphine following atropine was compared to the response to morphine alone, both with regard to the development of phase III-like activity as well as the motility response (comparing the number of contractions in the duodenum . 6 mm Hg for e ach 10-min period). Part E (b). Part C was repeate d in ® ve subjects, with atropine (10 m g/kg) injecte d 5 min before the initial bolus dose of morphine. Morphine was the n injecte d in bolus doses of 5, 5, and 10 m g/kg at 6-min intervals (or until phase III-like activity was recorded), the injections commencing 30 min following occurrence of a spontaneous phase III in the proximal duodenum. The response to morphine given afte r atropine was compared to the response to morphine in part C, with regard to the development of phase III-like activity. An alysis of Man om etric Tracin gs. All records were analyzed manually. Phase III activity, phase III-like activity, duodenal ª spasm,º and bursts of maximal contractility are de® ned in Table 1. Duration of phase III or phase III-like activity was take n from the point of onset of maximal contractility to the point of cessation of this maximal activity. Mean maximal amplitude was take n as the grand me an of the ave rage maximum amplitude in each subject during

2179

LEWIS T ABLE 1. D UODENAL M OTILITY P ATTERNS Duoden al phase III activity

Duodenal phase III-like activity

Maximal contractile activity occurring seque ntially in the duodenum, propagating aborally, and followed by a period of absent contractility (phase I).

Maximal contractile activity, with the onset almost simultaneous, propagating aborally, followed by a minimal period of absent contractility.

phase III. The rate of contraction was the ave rage number of contractions per minute me asured over a minimum of 2 min during e ach phase III from the onset of maximal activity, or as soon afte rward as the record was clear enough to allow counting of separate contractions. Gastric contractions we re analyze d in the two most distal gastric recording sites; more proximal gastric recording sites typically registered minimal or no contractile activity. The distal recording site was within 5 cm of the pylorus and ofte n recorded strong contractions; the next adjacent gastric recording site was 5 cm proximal and typically recorded ve ry we ak contractions (or no contractions if the distal contractions we re of low amplitude). Statistical signi® cance was measured by Student’s t te st, chi-square analysis, Fisher’s exact test, or McNe mar’s te st. V alues are expressed as me an 6 SEM .

Isolated bursts of maximal contractility

Duodenal spasm Simultaneous re petitive bursts of maximal contractility in all leads, not propagating and occurring for prolonge d periods (typically interrupted by gastric contractions, with brief periods of duodenal quiescence associated) .

Intermittent bursts of maximal activity not pre sent in all leads and not propagating.

RESULTS Part A: Mor ph in e vs Salin e In fu sion . During saline infusion, occasional phase III activity occurre d as anticipate d (Figure s 1 and 2). When morphine infusion was be gun, an increase in motility was typically re corded within a fe w minute s, with bursts of maxim al duode nal contractility, similar to phase III, occurring in all duode nal recordings in eight of the 10 subje cts within 15 min (P , 0.005 compare d to saline ) (Figure 1). In these e ight subje cts, this maximal duode nal contractility was similar to spontane ous phase III (Table 2), diffe ring from it in the following: (1) the

Fig 1. Duodenal phase III motor activity occurring during the infusion of saline (S) or morphine 40 m g/kg/hr (M) in normal human subjects. The shade d areas re present phase III, phase -III-like activity (maximal duodenal contractility. Note maximal contractility recurren tly occurring (*on two occasions in subjects 4 & 10, and ** on one occasion in subject 6) ; the lines joining the shade d areas re present transient inhibition of duodenal motility when gastric contractions occur. ***Recurri ng bursts of isolated maximal activity in subject 8 from 6 to 30 minutes following commence ment of morphine infusion (ne ver simultane ous in all duodenal leads).

2180

Digestive Diseases and Sciences, Vol. 44, No. 11 (Novem ber 1999)


Fig 2. (A) A spontaneous phase III occurring in both stomach and duodenum; the gastric contractions cease when duodenal motility reaches its maximum. G1 and G2 indicate two gastric recording sites 5 cm apart, while D1± D4 indicate four duodenal re cording sites at 5-cm intervals, with D1 being proximal and 5 cm from G2. (B) Phase-III-like activity occurring in response to intravenous injection of morphine (5 m g/kg). The arrow indicates the time of injection of morphine . G1 and G2 record gastric antral pressure while D1± D4 record duodenal pressure. The six re cording sites are numbe red from proximal to distal, and all are 5 cm apart.

T ABLE 2. CHARACTERISTICS

OF

D UODENAL P HASE III A CTIVITY A. Morphin e infusion (Part A) All spontaneous phase III in part A

Mean duration (sec) Time of onset of Phase III, 10 cm apart (sec) Time of ce ssation of Phase III, 10 cm apart (sec) Rate of contraction (pe r min) Maximum amplitude of contraction (mm Hg) *P ,

288 38.2 120.3 11.4 51.4

6

6

6

6

6

22 13.3 33.2 0.2 6.5

Initial phase III following morphine infusion 343 6

2 4.9 6 82.3 6 11.4 6 54.9 6

127 10.9* 21.4 0.1 2.5

IN

R ESPONSE

TO

MORPHINE

B. Morphine bolus injection (Parts C & D) Morphine Spontaneous 258 30.7 94.5 11.2 55.7

6

6

6

6

6

24 15.0 19.8 0.1* 2.1

Fasting 233 27.4 103.6 11.6 54.3

6

6

6

6

6

39 17.9 28.2 0.2 3.4

Fed 281 11.4 95.8 11.7 52.8

6

6

6

6

6

36 4.0 21.3 0.1* 3.6

0.05.

Digestive Diseases and Sciences, Vol. 44, No. 11 (November 1999)

2181

LEWIS

onse t was almost simultane ous during morphine infusion, and (2) the following phase I was abbre viate d, with freque nt vigorous contractions often recorde d in the 10 min following the e nd of morphine -induce d activity (neve r see n following spontane ous phase III activity) . In three of these e ight subje cts, this initial maximal phase III-like contractility occurring in re sponse to morphine infusion was more prolonge d than the bursts of contractility see n in the othe r ® ve subje cts; occasional short periods of duode nal inhibition (1± 3 min) were note d during these bursts of prolonge d activity occurring at the same time as re current large amplitude gastric contractions (Figure 3). (No recurring gastric contractions were observe d during maximal duode nal activity of spontane ous phase III activity) . This more prolonge d period of duode nal activity, sugge sting duode nal spasm, was not associate d with nause a or vomiting. Two of the 10 subje cts faile d to show maximal duode nal contractility, sugge stive of phase III-like activity within 15 min of commence ment of morphine infusion. In one subject (in whom a spontane ous phase III burst occurre d 7 min be fore the start of morphine infusion) , sporadic nonpropagating bursts of maximal duode nal activity in various leads occurre d, be ginning 6 min after morphine infusion be gan and re curring, until contractility more like phase III occurred 76 min afte r the start of morphine infusion. The othe r subje ct showe d no discernible response to morphine , with a typical phase III occurring 53 min following the start of morphine infusion. The mean time to onse t of any maxim al duode nal activity following the be ginning of morphine infusion in the nine who appe are d to re spond to morphine with bursts of maximal contractility was 7 min 35 se c 6 3 min 14 se c (giving a mean dose of morphine infuse d until the start of maximal contractility of 5.1 m g/kg) . The motility patte rn se en during saline infusion was dissim ilar, mostly be ing phase II, with six phase IIIs occurring within this 90-min infusion pe riod (Figure s 1 and 2); the e arlie st that phase III occurred from the start of saline infusion was 20 min 9 sec. Table 2 compare s spontane ous phase III activity occurring during saline infusion with the initial phase III-like activity occurring during morphine infusion. Part B: Morph in e Plu s Naloxon e vs Mor phin e In fusion . The six subje cts studie d all had shown phase III-like activity in part A soon afte r starting morphine infusion. When naloxone was infuse d at 40 m g/kg/hr, no increase in duode nal contractility in ® ve of the six subje cts was see n (including no phase III-like activity) whe n morphine was infuse d; the sixth subje ct deve l-

2182

ope d phase III-like activity 6 min from the start of infusion of morphine plus naloxone , with a se cond phase III-like burst occurring 18 min late r. Naloxone thus signi® cantly impaire d the e ffe ct of morphine in initiating phase III-like activity (P , 0.05) . Part C: Low-Dos e Bolu s Mor phin e Injection Followin g Sp on tan eou s Ph ase III. Morphine , inje cted as a bolus 30 ± 42 min following a spontane ous phase III, initiate d premature phase -III-like activity in all six subje cts (Figure 2). The burst of maximal duode nal activity appe ared ide ntical to spontane ous phase III activity (Table 2), exce pt in one subje ct the re was a brief inhibition of maximal activity during the phase III burst at the time of occurrence of a large gastric contraction. The dose require d to initiate the phase III-like activity see n was 5 m g/kg in four subje cts, 10 m g/kg in one subje ct, and 20 m g/kg in one subje ct, with phase III-like activity occurring 101 6 27 sec afte r morphine inje ction. In contrast, during part A saline infusion, a spontane ous phase III was followe d within 60 min by a second spontane ous phase III on only one occasion (subje ct 2 at 38 min) (P 5 0.006, morphine induce d vs spontane ous phase III occurrence). Part D: Low-Dos e Bolu s Morp h in e Injection Durin g Fed State. In all ® ve subje cts, inge stion of the liquid meal initiate d the fe d patte rn (repe ated duode nal contractions) , with only rare gastric contractions be ing obse rved (probably be cause most contractions occurring in response to the liquid meal were not lume n-oblite rating, and so not re cordable by pe rfused tube s). During the fed state , at 30 ± 40 min following the meal, all subje cts re sponde d to a morphine bolus with phase III-like duode nal activity, three in response to 5 m g/kg, and two in re sponse to 10 m g/kg (Figure 4), occurring 82 6 29 sec after the morphine bolus inje ction. In a comparable group of six volunte ers, only one spontane ous phase III occurre d in the hour following the same liquid meal (at 55 min) (P , 0.05) . Part E: Mor phin e Plu s Atrop in e. When intrave nous atropine , 10 m g/kg, was give n before morphine intrave nously, morphine intrave nous infusion induce d e ither no discernible increase in contractions or sporadic nonpropagatory bursts of maximal duode nal activity. The patte rn of activity did not re semble phase III activity. Atropine thus impaire d the de velopme nt of phase III-like motility in re sponse to morphine infusion (P , 0.05) . Atropine inje ction prior to the infusion of morphine produce d a signi® cant re duction in duode nal motility for the ® rst 10 min of morphine infusion, but not during subse que nt 10-min time periods. Whe n atropine was give n be fore the Digestive Diseases and Sciences, Vol. 44, No. 11 (Novem ber 1999)


Fig 3. (A) Re curring duodenal maximal contractility interrupted by isolated gastric contractions occurring during the infusion of morphine (40 m g/kg/hr) . The numbers 1± 6 indicate recording sites 5 cm apart, with G 5 gastric, D 5 duodenal. (B) Repe ated maximal activity se en in both the stomach and duodenum during infusion of morphine (40 m g/kg/hr) , with little e vide nce of organisation into typical phase III activity. G 5 gastric and D1± D4 5 duodenal re cording sites, from proximal to distal, 5 cm apart. The arrow indicates the time of commence ment of morphine infusion. Note the prominent gastric contractility.

bolus inje ction of morphine , the re was abse nce of phase III-like activity (nonsigni® cant, compare d with morphine give n alone ). The patte rn of re sponse was similar to that se en when atropine was give n prior to the infusion of morphine . Digestive Diseases and Sciences, Vol. 44, No. 11 (November 1999)

Gastric Respon ses. Gastric phase III was conside re d to be pre se nt if at least three gastric contractions at the maxim al rate were re corde d at the time of onse t of duode nal phase III. At times, gastric phase III pre ce de d both spon tan e ous and m orphin e -

2183

LEWIS

Fig 4. Phase -III-like activity occurring in re sponse to intrave nous injection of morphine following a liquid me al. The arrow indicates the time of injection of morphine (5 m g/kg). G 5 gastric pre ssure , while D1± D5 re cord duodenal pre ssure at 5-cm intervals.

induce d duode nal phase III activity, although le ss fre que ntly prese nt (not signi® cant) with morphine induce d phase III (Table 3). O n seve ral occasions, during more prolonge d morphine -induce d duode nal bursts, gastric contractions re curre d associate d with brie f periods of duode nal inhibition. These large gastric contractions always produce d duode nal inhibition (Figure 3). O ccasionally, re peate d gastric contractions also occurred following these e pisode s of duode nal spasm (Figure 3). Repe ated gastric contractility was neve r se en after the onse t of a spontane ous duode nal phase III. DISCUSSION The MMC occurs re pe ate dly during fasting in the human uppe r gastrointe stinal tract and is abse nt following a meal for a prolonge d but variable period of time (1± 3, 22, 23). The most ide nti® able portion of the MMC is phase III, which propagate s throughout the intestine . The fre que ncy of phase III is ve ry variable , both within and be twee n subje cts, re curring T ABLE 3. G ASTRIC P HASE III A SSOCIATED

SPONTANEOUS P HASE III*

WITH

A. Morphine infusion (part A)

All spontaneous Morphine-induced

usually at 50 to 150-min intervals (1± 3, 22, 24) , although shorte r and longe r cycle s are se en. Morphine has bee n shown to induce premature phase III activity, both in dogs (8, 9, 25, 26) and in humans (in postope rative studie s) (10, 11) . This study con® rms that morphine is able to stimulate motility and induce phase III-like activity in normal he althy humans not re covering from surge ry and shows that the human duode num is re sponsive to the motor stimulating e ffect of morphine give n in small dose s (as little as 5 m g/kg) . Intrave nous morphine induce s incre ase d motility typically similar to spontane ous phase III activity, although the onse t of this activity sugge sts that morphine may be stimulating multiple le vels within the duode num simultane ously. The re is little e vide nce of a phase I patte rn following this maxim al activity. O n occasion, the maxim al activity induce d is more prolonge d than this usual phase III-like activity; these prolonge d bursts are atypical in the ir duration, and re curring gastric contractions occur that inhibit duode nal contractions. This re sponse doe s not appe ar AND

MORPHINE -INDUCED D UODENAL

B. Morphine bolu s (parts C and D)

C. All spontaneou s² vs all morphine-in duced³

Present

Absent

Present

Absent

Present

Absent

3 2

3 8

2 0§ 2¶

4 6§ 4¶

5 3

11 19

* P 5 NS. ² All phase III activity not occurring either during infusion of morphine or following injection of morphine . ³ Initial with morphine infusion and all following morphine bolus. § Fasting. ¶ Fed.

2184



to be the motility corre late of nause a and vomiting, as none of the volunte e r subje cts experienced the se symptoms, and the typical motor patte rn associate d with nause a and vomiting is not se en (27, 28) . This prolonge d re sponse (spasm) may be a similar but more inte nse response than the more typical phase III-like re sponse to morphine [compare the re sponse of the duode num to slow and rapid intraduode nal infusion of acid (2)]. The re sponse of the je junum and ile um to morphine was not addre sse d in this study. Gastric contractions fre que ntly pre cede spontane ous phase III activity, but ne ver re cur during spontane ous phase III activity (2, 3). There is no evide nce for a dire ct effe ct of morphine to stimulate gastric contractions: in the dog stomach, morphine give n by direct intraarte rial inje ction only produce s inhibition of gastric contractions, without any stimulation see n (29, 30) . There is little available evide nce in humans, but antral hypomotility is pre sume d to be the cause of the delaye d gastric emptying se e n with morphine (31) . The cause of the recurring gastric contractions se e n with intrave nous morphine is not cle ar but could be due to motilin re le ase [both duode nal phase III and intrave nous morphine have bee n reporte d to re le ase motilin (32, 33) , and motilin is able to incre ase gastric motility (34, 35) ]. The intermitte nt inhibition of duode nal maximal contractility by recurring gastric contractions during the se prolonge d duode nal bursts is probably mediate d via inhibitory ne rve pathways trave ling from the stomach to the duode num (36) . Antral and duode nal phase III activity is inhibite d following a meal (23) ; morphine is able to ove rcome this inhibition and to induce phase III-like activity, similar to the e ffe ct see n in dogs (18) . This report doe s not addre ss whe re morphine is acting to induce phase III activity. Morphine increases gastrointe stinal motility by actions both on the central ne rvous system and by periphe ral actions on the inte stine (25) . Howe ve r, its ability to induce phase III activity appe ars to be a periphe ral e ffe ct (25) . Howe ver, morphine is acting via opioid receptors as it is blocke d by a dose of naloxone reporte dly spe ci® c for opioid receptors (25, 30) . Atropine in the mode rate dose use d here is probably insuf® cient to produce comple te muscarinic blockade ; this dose blocke d the phase III-inducing effe ct of morphine , without ne cessarily pre venting increased motility. Inhibition of nitric oxide synthase leads to pre mature phase III activity (37) , and morphine may act to disinhibit intrinsic nitric-oxide releasing nerve s, producing an increase in motility (38) , so that the action of atropine see n here may be an indire ct e ffect. Digestive Diseases and Sciences, Vol. 44, No. 11 (November 1999)

In summary, morphine is able to initiate maxim al bursts of contractility in the duode num of he althy human subje cts similar to pre mature phase III-like activity, both in the fasting and fe d state. While gastric phase III is occasionally associate d with morphine -induce d phase III-like activity, recurring gastric contractions may also occur along with prolonge d duode nal bursts of contraction. The induction of phase III-like activity is mediate d via opioid receptors, and abolishe d by muscarinic choline rgic re ceptor antagonists. The possible physiological role of the motility re sponse to morphine re mains uncle ar; opioid receptors have be e n reporte d e ithe r to be important in the induction of phase III (with the opioid antagonist naloxone de laying its occurre nce, but not pre venting it) (24, 26) , or to play no role at all (with naloxone having no effect) (39, 40) . This que stion was not addre ssed in this study. Thus, it re mains uncle ar if intrinsic opioid re le ase plays a role in controlling duode nal motility. REFERENCES 1. Vantrappen G, Jansse ns J, Ghoos Y: The interdige stive motor comple x of normal subjects and patients with bacte rial ove rgrowth of the small intestine. J Clin Inve st 59:1158 ± 1166, 1977 2. Le wis TD, Collins SM, Fox JE, Daniel EE: Initiation of duode nal acid -induce d m otor com ple xe s. Gastro e nte rology 77:1217± 1224, 1979 3. Thompson DG, Archer L, Gree n WJ, Wingate DL: Fasting motor activity occurs during a day of normal meals in healthy subjects. Gut 22:489 ± 492, 1981 4. Ke rlin P, Phillips S: Variability of motility of the ileum and jejunum in he althy humans. Gastroe nterology 82:694 ± 700, 1982 5. Sarna SK: Cyclic motor activity; migrating motor comple x: 1985. Gastroente rology 89:894 ± 913, 1985 6. Vantrappen G, Jansse ns S, Pe eters TL, Bloom SR: Motilin and the interdige stive migrating motor comple x in man. Dig Dis Sci 24:497± 500, 1979 7. Thomas PA, Kelly KA, Go VLW: Doe s motilin regulate canine interdigestive gastric motility. Dig Dis Sci 24:577± 582, 1979 8. Konturek SJ, Thor P, KroÂ l R, De mbinski A, Schally AU: In¯ ue nce of methionine-e nke phalin and morphine on myoele ctric activity of small bowel. Am J Physiol 238:G384 ± G389, 1980 9. Sarna S, Northcott P, Be lbeck L: Me chanism of cycling of migrating myoelectric complexe s: Effects of morphine. Am J Physiol 242:G588 ± G595, 1982 10. Ingram DM, Catchpole BW: Effe ct of opiates on gastroduodenal motility following surgical ope ration. Dig Dis Sci 26:989 ± 992, 1981 11. Waterfall WE: E lectrical patte rns in the human jejunum with and without vagotomy: migrating myoe lectrical complexes and the in¯ ue nce of morphine. Surgery 94:186 ± 189, 1983 12. Bueno L, Fioramonti J, Rayne r V, Ruckebusch Y: E ffects of motilin, somatostatin, and pancreatic polypeptide on the mi-

2185

LEWIS

13.

14.

15. 16.

17.

18.

19. 20.

21.

22.

23.

24.

25.

26.

grating myoele ctric complex in pig and dog. Gastroe nterology 82:1395± 1402, 1982 Konture k SJ, Siebe rs R: Role of histamine H 1 - and H 2 receptors in myoele ctric activity of small bowel in the dog. Am J Physiol 238:G50 ± G56, 1980 Sami R, Funakoshi A, Vinik AI, Owyang C: Plasma motilin conce ntration and interdigestive migrating motor complex in diabe tic gastropare sis: Effect of me toclopramide. Gastroente rology 88:492± 499, 1985 Otterson MF, Sarna SK: Gastrointestinal motor e ffects of erythromycin. Am J Physiol 259:G355± G363, 1990 Sarna SK, Soe rgel KH, Koch TR, Stone JE, Wood CM, Ryan RR, Arndorfer RC, Cavanaugh JH, Nellans HN, Lee MB: Gastrointestinal motor effects of e rythromycin in humans. Gastroenterology 101:1488 ± 1496, 1991 Fox JET, Track NS, Danie l EE: Re lationship of plasma motilin conce ntration to fat ingestion, duodenal acidi® cation and alkalinization, and migrating motor complexe s in dogs. Can J Physiol Pharmacol 59:180 ± 187, 1981 Sarna SK, Condon RE: Morphine-initiated migrating myoe lectric complexe s in the fed state in dogs. Gastroe nterology 86:662± 669, 1984 Danie l EE, Costa M, Furne ss JB, Ke ast JR: Pe ptide neurons in the canine small intestine. J Comp Neurol 237:227± 238, 1985 Polak JM, Bloom SR, Sullivan SN, Face r P, Pe arse AG: Enkephalin-like immunore activity in the human gastrointestinal tract. Lance t 1:972± 974, 1977 Fox JET, Daniel E E: Activation of endoge nous opiate pathways in canine small intestine by ® eld stimulation and motilin. Am J Physiol 253:G189 ± G194, 1987 Re es WDW, Malagale da J-R, Miller LJ, Go V LW: Human interdigestive and postprandial gastrointe stinal motor and gastrointestinal hormone patterns. Dig Dis Sci 27:321± 329, 1982 Wilson P, Pe rdikis G, Hinde r RA, Re dmond EJ, Anselmino M, Quigley E MM: Prolonge d ambulatory antroduodenal manometry in humans. Am J Gastroente rol 89:1489 ± 1495, 1994 Re es WDW, Sharpe GR, Christo® des ND, Bloom SR, Turnbe rg LA: The effe cts of an opiate agonist and antagonist on the human upper gastrointe stinal tract. Eur J Clin Invest 13:221± 225, 1983 Telford GL, Hoshmonai M, Mose s AJ, Szurszewski JH: Morphine initiates migrating myoele ctric complexe s by acting on peripheral opioid receptors. Am J Physiol 249:G557± G562, 1985 Telford GL, Condon RE , Szurszewski JH: Opioid re ce ptors and the initiation of migrating myoele ctric comple xes in dog. Am J Physiol 256:G72± G77, 1989

2186

27. Lang IM, Sarna SK, Condon RE : Gastrointestinal motor correlate s of vomiting in the dog: Quanti® cation and characte rization as an independe nt phenomenon. Gastroenterology 90:40 ± 47, 1986 28. Sarna SK: Giant migrating contractions and their myoele ctric corre lates in the small intestine. Am J Physiol 253:G697± G705, 1987 29. Fox JET, Danie l EE: Exoge nous opiates: Their local mechanisms of action in the canine small intestine and stomach. Am J Physiol 253:G179 ± G188, 1987 30. Danie l EE , Fox JE T, Allescher H-D, Ahmad S, Kostolanska F: Peripheral actions of opiates in canine gastrointe stinal tract: Actions on ne rves and muscles. Gastroe ntol Clin Biol 11:35B43B, 1987 31. Duthie DJR, Nimmo WS: Adverse effe cts of opioid analgesic drugs. Br J Anae sth 59:61± 77, 1987 32. Sarna S, Chey WY, Condon RE, Dodds WJ, Myers T, Chang TM: Cause-and-e ffect relationship betwee n motilin and migrating myoele ctric complexes. Am J Physiol 245:G277± G284, 1983 33. Poitras P, Boivin M, Lahaie RG, Trudel L: Re gulation of plasma motilin by opioids in the dog. Am J Physiol 257:G41± G45, 1989 34. Hall KE, Gre enbe rg GR, El-Sharkawy TY, Diamant NE : Re lationship betwee n porcine motilin-induce d migrating motor comple x-like activity, vagal integrity, and endoge nous motilin rele ase in dogs. Gastroente rology 87:76 ± 85, 1984 35. Mizumoto A, Sano I, Matsunaga Y, Yamomoto O, Itoh Z : Me chanisms of motilin-induce d contractions in isolated pe rfused canine stomach. Gastroente rology 105:425± 432, 1993 36. Re ddy SN, Danie l EE: Neural control of duodenal motor inhibition by antral contractions in dogs. Am J Physiol 258:G24 ± G31, 1990 37. Russo A, Frase r R, Adadi K, Horowitz M, Boe ckxstae ns G: Evide nce that nitric oxide mechanisms regulate small intestinal motility. Gut 44:72± 76, 1999 38. Fox-Thre lkeld JET, Daniel EE, Christrinda F, Itruly V J, Cipris S, Woskowska Z : Identi® cation of me chanisms and sites of actions of mu and de lta opioid re ce ptor activation in the canine intestine. J Pharmacol E xp Ther 268:689 ± 700, 1994 39. Borody TJ, Quigley EMM, Phillips SF, Wienbe ck M, Tucke r RL, Haddad A, Zinsmeister AR: Effects of morphine and atropine on motility and transit in the human ileum. Gastroente rology 89:562± 570, 1985 40. Sarna SK, Lang JM: Dose- and time-de pe nde nt biphasic re sponse to morphine on migrating myoe lectric complexe s. J Pharmacol Exp The r 234:814 ± 820, 1985
