Indian Journal of Experimental Biology Vol. 47, April 2009, pp. 229-244

Review Article

Migrating motor complex in biological sciences: Characterization, animal models and disturbances

Krzysztof W. Romański Department of Animal Physiology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, 31 Norwida str., 50-375 Wrocław, Poland

The migrating motor complex (MMC) occurs in most mammals and birds and is organized during the fetal life. In some species, like ruminants and other herbivores, it is not abolished by feeding but its character and controlling mechanisms do not vary considerably from other animal species. However, the mechanisms controlling the MMC are complex and incompletely recognized. The central nervous system exerts rather modulatory effects upon the MMC and the role of the in the initiation and propagation of the MMC is crucial. The hormones appear mainly to disrupt and convert the MMC cycle into the fed pattern. Several types of the disturbances of the MMC cycle and its phases have been described in various pathophysiological conditions. However, it can be more suitable to identify and describe the given MMC abnormality than to establish the rules of the MMC behavior in the course of the gastrointestinal diseases.

Keywords: Migrating motor complex, Neurohormonal control, Non-ruminants, Ruminants

In man and other monogastric species, during the allows to maintain the labile balance between the interdigestive period, also called the fasting state, the secretory and absorptive processes in the fasting state majority of previously ingested foods is already what in turn prevents accumulation of the digestive utilized in the and small bowel. In normal juices and, in consequence, the arrival of conditions the interdigestive state can be simply gastrointestinal motor disturbances. The existence of defined as time period during which the stomach and some active contractions hampers the bacterial are almost empty. However, the overgrowth at least in the proximal small bowel and indigestible food remnants, bacteria and cellular aboral transport of chyme protects against the debris can still occur in the gastrointestinal lumen. It gastrointestinal mucosal damage and decreases the is also possible that in the fasting period small reflux frequency. During the interdigestive state these portions of fluid and foods are ingested. The secretion functions occur in the cyclic (interrupted) fashion. of the digestive juices, i.e. the gastric and pancreatic Mixing of the luminal content is less intense than after juice, and intestinal fluid, is incompletely feeding and well organized propulsion is adjusted to hampered during the interdigestive state in order to the amount of chyme stocked up inside the bowel. continue the digestive processes in the . Since these cycles move down along the bowel it was There are several physiological needs to sustain the proposed to call them the migrating motor complexes motor function in the interdigestive period. The motor (MMCs) or the interdigestive migrating motor function ensures mixing, transport, , and complexes2 and the MMC concept is commonly in absorptive processes of the relatively small amounts use. The presence of the quiescent period in the MMC of luminal content during this period. The movements cycle allows muscle to rest and regeneration. Its active of the gastrointestinal wall facilitate the intramural phases ensure the physical smooth muscle exercise and blood and lymph flow, provide the smooth muscles exhibit some trophic and regulatory aspects. exercise, and probably also release a regulatory Thus the physiological role of the MMC warrants its 1 substances from the endocrine mucosal cells . This scientific interest. The MMC cycle can be included into ultradian rhythms and the rhythmic concept of ______the gastrointestinal motility organization was Telephone: +48-71-3205422 3,4 Fax: +48-71-3281567 characterized . The historical background of the MMC 5 E-mail: [email protected] is already reported and hence not repeated here. 230 INDIAN J EXP BIOL, APRIL 2009

The aim of this communication is to present the Coordination of gastrointestinal functions during current knowledge on the interdigestive motility of interdigestive state the stomach and small intestine with special emphasis The interdigestive motility pattern can ensure the on the MMC, its control and possible disturbances digestive transport due to the coordination of principally addressed to the medical experimental and gastrointestinal contractions within the cycle and due clinical contributors. to the coordination of its function with other functions of the digestive system during the interdigestive state General characteristics of MMC in non-ruminants and ruminant species, and also The MMC cycle occurs in the majority of during the digestive state in ruminants. mammals and birds during the whole life4,6. In most Coordination of the gastrointestinal motility within monogastric animals the pattern is observed during the MMC—There are three basic levels of the interdigestive state but in ruminants it is not coordination of the gastrointestinal motility (MMC) in disrupted after feeding7. The MMC contains three the interdigestive state. First comprises the or four phases. During phase I the relative lack of relationship between the pacessetter potentials (slow contractions is present. In phase II, contraction waves) and the spike bursts. The frequency of the incidence gradually increases reaching the slow waves in the given gastrointestinal region maximum during phase III of the cycle. Phase IV of determines the frequency of the spike bursts and the MMC is not always observed. Species contractions during phase II, and especially during differences of the MMC are rather quantitative than phase III of the MMC when the incidence of the spike qualitative (Table 1) and the differences in cycle bursts and contractions are greatest. During phase II and phase duration are related to the species- of the MMC the presence of the slow waves facilitates specific features of the . The the occurrence of the spike bursts and contractions in most precise identification criteria of MMC were response to weak stimuli, thus the gastrointestinal elaborated in man (Table 2). In pigs the MMC response to the given stimulus appears to be more arrival is related to the feeding frequency. In non- precise than without the slow waves8. The ruminant herbivores the interdigestive periods are intrasegmental coordination represents the second usually longer than in ruminant herbivores and level of coordination of the MMC cycles. This means duration of the MMC is longer. In herbivores the that within the given gastrointestinal shorter or longer MMC cycles accelerate the digestive transport segment the single spike bursts and contractions through the relatively long gastrointestinal tract. In (or their lack) behave in well-organized fashion9,10. In the myoelectrical recordings the organization of the the course of phase II of the MMC the series of MMC is similar to that in motor recordings. It contractions migrate along the bowel in well- occurs not only in the gastric region and in the organized fashion and their presence is apparently entire small bowel but is also observed in the related to the luminal stimuli. Similar situation is hindgut. Thus in mammals and birds the MMC during phase III. The mode of migration of the spike represents one of the main motility patterns. bursts in the small intestine is the best illustration of However, there are some methodological this physiological event. The third level comprises the difficulties in MMC recording (Table 3). intersegmental coordination of the MMC. This can be

Table 1 — Species differences in the jejunal MMC recorded with an electromyographical method in fasted subjects

Duration (min) MMC cycle Phase I Phase II Phase III Phase IV Ref. Man 122 – 172 20 – 90 35 – 135 2 – 11 133 Dog 90 – 114 13 – 72 15 – 74 5 – 7 2 – 4 134 Pig 75 – 80 10 – 20 ~ 50 ~ 5 7 Rat 13 – 21 4 – 7 5 – 7 4 – 5 135 Rabbit 136 – 153 5 – 10 ~ 90 – 120 5 – 30 0 – 20 136 Guinea pig 48 – 117 8 – 16 36 – 99 3 - 5 137 Sheep* 65 – 105 19 – 57 35 – 53 4 – 7 138,139 Gallus# 41 - 114 3 – 10 6 *in non-fasted animals, #in the proximal ROMAŃSKI: MIGRATING MOTOR COMPLEX IN BIOLOGICAL SCIENCES 231

Table 2 —The applied criteria for identification of the MMC cycle and its phases in the human small intestine using the manometric techniques

MMC cycle Phase I Phase II Phase III Phase IV Ref.

1. Cyclic arrival of Lack of motor Irregular Regular contractions more Short period of 140 the MMC activity contractions less than 10/min lasting over 2 declining phases than 10/min min and appeared sequentially activity after in both duodenal ports phase III 2. Not specified <1 contraction of 1-10 contractions Uninterrupted >2 min periods 141 ≥ 10 mm Hg per per min of irregular of regular phasic contractions min frequency and propagated distally at amplitude frequency 10-12 cpm 3. Cycle of phases Less than three Irregular Regular pressure waves at the 116 I-III while phase pressure waves contractile activity slow wave frequency lasting III is the most every 10 min before phase III for about 5 min, migrating distinctive aborally 4. Cycle containing Motor quiescence Motor activity Regular pressure waves, 10.5- 142 phase III period with below the phase III 14/min for at least 2 min contractions not frequency but more more than 2/10 than 2 min and preceded contractions/10 by phase III min 5. Cycle containing Motor quiescence Periods when phase ≥ 10 pressure waves per min 143 phases I – III <3 pressure waves I and phase III are for ≥ 2 min extending over per 10 min absent ≥ 4 sideholes (40 cm) 6. Phases I – III No contractions, More than 2 Rhythmic contractile activity 144 starting just after contractions per 10 with frequency 10-12 cpm the end of phase min but less than during 3 min, propagated III 10 per 1 min down and followed by phase I 7. Not specified Complete Immediately Uninterrupted phasic 145 quiescence precedes phase III, contractions ≥ 2 min recurred irregular pressure at a frequency 10-12 cpm, waves propagated aborally

Table 3 ⎯ Characteristics of the principal in vivo methods applicable for the MMC recording in man and animals Method Advantages Disadvantages

Electromyography 1. Recording of the spike bursts and slow waves 1. Harmful for the mucosa (suction electrodes, i.e. possible. electromanometry) 2. Recording rather from the given site. 2. Wall movement during contractions. 3. Rather non-invasive method (no laparotomy is 3. Longer recording difficult. necessary). Electromyography 1. Recording of the spike bursts and slow waves 1. The invasive method requiring (electrode implantation) possible. laparotomy. 2. Precise recording from the given site. 2. Time-consuming method.

Manometry 1. Recording of contractions rather from the given area. 1. Not precise recording: (pressure recording) wall 2. Non-invasive method. a) movements of the wall during contractions, b) possible movements of the recording tube.

Implanted force 1. Precise recording of the mechanical activity. 1. The invasive method requiring laprotomy. transducers 2. Possible recording of phasic and tonic components. 2. Time-consuming method. 3. Possible separate recording from the longitudinal and circular smooth muscle layers. 232 INDIAN J EXP BIOL, APRIL 2009

outlined with the mutual relationships among the preserved limited secretory activity enables the digestion adjacent regions including lower esophageal sphincter, of the food remnants and cellular debris and also stomach, pylorus, duodenal bulb, the duodenum, the exhibits some regulatory role. These digestive processes , the ileum and the ileo-cecal sphincter. The occur during the non-propulsive phases of the MMC. myoelectric and motor cooperation between these The cyclical intensity of the interdigestive motor activity regions allow for thornless migration of phase III of the must ensure the optimal transit of chyme in the small MMC in organized fashion through the longer bowel and facilitate the presence of optimal absorptive segments of the gastrointestinal tract. Migration of processes33,34. Phase III of the MMC is the major driving phase III from the stomach toward the duodenum is force to transport the chyme aborally, towards the undisturbed since the pylorus is almost completely hindgut. As it can be expected, changes in motility and open during interdigestive antral contractions11. Phase secretion observed during the course of the MMC cycle III migrates often to the terminal ileum and the luminal alter the absorption dynamics in the gut. The villous content is transported into the colon12. The application motility alterations might participate in these effects. of some surgical procedures confirm these findings and Thus, the interdigestive motility may contribute state that the gastrointestinal wall continuity is significantly to the balance between absorptive and responsible for this coordination13-15. secretory function in the small intestine35. Figure 1 Other motility patterns present within the MMC summarizes the mutual relationship between the MMC cycle—The MMC cycle is coordinated with other and gastrointestinal transport, secretion and absorption. motility patterns. As already mentioned, the MMC cycle Control of the MMC cycles is believed to be replaced after feeding by the fed pattern Control of the MMC cycles is very composed and in several non-ruminant species but it is not known engages the myogenic, neural and hormonal whether its fragments are not preserved. Other patterns mechanisms (Fig. 2). It can be stated that the were observed in the course of normal MMC cycle. It character of the MMC cycle is more precisely was reported that the minute rhythm arrives during late described than its controlling mechanisms. phase 1 and during the whole phase 2 of the MMC16,17. Furthermore, the presence of giant spike bursts, ultrarapid spike bursts, and repetitive bursts of action potentials were described18-20. These patterns usually coexist with the MMC and arrive during its phase II. Coordination of the MMC with other gastrointestinal functions—Soon after the MMC concept was established it was found that the duodenal pH is increased around the onset of the duodenal phase III21. The fluctuation of intraluminal pH indicated the presence of periodic changes in secretory functions during the interdigestive Fig. 1—Mutual relationships between the MMC and main gastrointestinal functions. state. Thus, during the years 1977-1980 couple of reports appeared presenting the studies upon the fluctuations in gastric, pancreatic and biliary secretions in man and dog in accordance with the MMC22-27. These events were called the secretory component of the MMC. The authors found the relatively small but significant increases in and secretion from the stomach and bicarbonate, amylase and bile inflow into the duodenum as compared with the digestive period. These results were confirmed in the later studies in man and animals28-32. The increase in gastric and biliary secretions occurred in the second half of the duodenal phase II and the increase in pancreatic secretion was rather at the end of phase II of the Fig. 2—General scheme of the neurohormonal control duodenal interdigestive cycle. It seems reasonable that mechanisms of the interdigestive motility. ROMAŃSKI: MIGRATING MOTOR COMPLEX IN BIOLOGICAL SCIENCES 233

The myogenic control of the MMC—The myogenic nocturnal interdigestive cycle is reversibly modified, mechanisms comprise all the factors influencing especially in normal conditions41. Another type of directly or originating from the smooth muscle cells. physiological experiments (sham feeding) showed Beside the factors affecting directly the smooth that the MMC cycles were also not abolished by muscle cell metabolism, the most important myogenic central mechanisms and in the post-sham-fed period mechanism is related to the intramural pacemaker the reappearance of phase III was retarded42. cells called the interstitial cells of Cajal (ICCs)36. Pharmacological experiments comprise the effects They induce the slow waves thus facilitating the of central administration of the various arrival of the spike bursts and contractions, participate pharmacological substances on MMC. Injections of in neural impulse transmission within the enteric different hormones like neurotensin, nervous system, and act as mechanoreceptors. Due to or induced variable (modulatory or the presence of hormonal receptors on ICCs and disrupting) effects on the MMC43,44. More recent data connections between the ICCs and peptidergic indicate that the destruction of noradrenergic neurons neurons, they may participate in the neurohormonal by 6-hydroxydopamine administered intracisternally, control of the gastrointestinal motility37,38. It is clear intracerebroventricularly and close to the locus that these mechanisms comprise both digestive and ceruleus exerted limited modulatory effects upon the interdigestive motility. Thus the incidence of the MMC cycle45,46. spike bursts and contractions during the MMC cycle Surgical experiments including sympathectomy, might be dependent on these mechanisms although superior and inferior mesenteric ganglionectomy as the detailed relationships remain unknown. well as total extrinsic denervation of the gut did not Nervous control of the MMC—Currently there is no abolish the MMC and these findings were doubt that the nervous control of the MMC is crucial summarized by the authors stating that it is unlikely for its initiation and modulation. It comprises the that the MMC is under the central nervous system 47 evident neural responses owing to the action of control . Similar results were obtained by Johnson et 48 neuromediators and interplay among central and al. who utilized the canine model with the peripheral modulators of the non-adrenergic non- autonomically denervated jejunum. The MMC cycles cholinergic (NANC) system as well as the hormones were preserved with the increased frequency. (principally peptide hormones)39,40. Among the The final group of the experiments illustrating the nervous control of the MMC, central and peripheral central effects upon the MMC comprises some controlling mechanisms can be distinguished. abnormalities within the central nervous system Central nervous control of the stomach and small involving the interdigestive motility alterations. Stress intestine mainly comprises the effects mediated by seems to represent the most distinct example. As it extrinsic innervation of these regions, namely vagal was already stated above, the destruction of central and sympathetic nerve-related influences, i.e. the noradrenergic neurons did not exert substantial effects controlling functions steered by central part of the on the MMC. However, the limbic system represents autonomic nervous system. These influences an important locus of the central control of intestinal 49 mediated by the efferent nerves occur mostly as the function . It also plays a role in the control of response to central effects and peripheral (afferent) emotions including stress reactions. Prolonged stress stimuli from the gastrointestinal tract. One of the inhibits the MMC cycle depending on the type, 50 incompletely resolved questions is what is the precise intensity, and duration of stress . When the stressor role of the central vs. peripheral nervous impacts in power is substantial, inhibition of the MMC can be the control of the MMC cycle. There is an increasing evident. knowledge focusing on the role of the central nervous Therefore, the central nervous system, in most system in the control of the MMC that comprises the cases, appears to modulate the MMC cycle but it can scientific evidence derived from physiological, also initiate and abolish the interdigestive motility pharmacological, surgical and clinical experiments pattern. Since complexes arriving in the stomach and observations. depend principally on input from cholinergic enteric Physiological experiments performed in humans neurons (including vagal efferent fibers), those revealed, for example, that the slumber does not originating in the small intestine depend rather on abolish the MMC although it is obvious that the input from noncholinergic enteric neurons51. Thus, the 234 INDIAN J EXP BIOL, APRIL 2009

central nervous system may control directly, although inferred from these studies that the neurons of the not exclusively, the gastric MMC and its influence on enteric nervous system play a crucial role in the small-intestinal MMC remains rather wobbly. control of gastrointestinal MMC. Peripheral nervous control of the MMC—The Neurohormonal factors contributing in the control question of the role of intrinsic gastrointestinal of the MMC—The nicotinic and muscarinic control of innervation in the control of the MMC seems to be gastrointestinal motility is well known. The devoid of basic controversy and is believed to be antimuscarinic drug atropine and the ganglionic greater than the extrinsic innervation. It has been blocker hexamethonium generally inhibit motor recognized that, at least in monogastric animal activity in the gastrointestinal region in monogastrics species, some intramural presynaptic neurons have and ruminants53-55. Similar effects were obtained internal clocks generating the MMC when little or no when atropine or hexamethonium were administered nutritional load is present in the stomach and small locally56. Thus, pharmacological experiments confirm intestinal lumen12. Figure 3 presents the general the importance of the cholinergic system in the scheme of composed peripheral control mechanisms. control of the interdigestive motility. Complete neural isolation of the stomach can The role of adrenergic nerves in the regulation of extinguish the MMC cycles. In spite of that these the MMC is rather modulatory alhough some of its cycles, originating in the stomach, may depend on meaningful influences upon the gastrointestinal input from cholinergic enteric neurons apart from the motility, including the MMC cycle, have been 4,51 other factors . These intramural neurons are most described57,58. The sympathetic system is understood probably responsible for the initiation and migration as the natural competitor of the parasympathetic of the MMC as well as for the disruption of the system in the control of physiological functions but in 4,12,52 MMC, at least in the great part . It can thus be respect to the MMC it does not seem to be the case59,60. Since there are relatively few studies reported, the effect of the adrenergic system upon the MMC still remains largely unknown. There are several adrenergic receptor subtypes60 and their role in the control of the MMC has been incompletely recognized. Administration of the adrenergic substances induced inconsistent effects upon the MMC. Isoprenaline in fasted humans61 and isoproterenol in fed dogs62, the unspecific β-agonists, inhibited or induced phase III of the MMC, respectively while propranolol did not evoke any significant changes in phase III of the MMC61. Studies upon the rat small intestine revealed that isoprenaline inhibited the MMC cycle and induced irregular spiking activity and this effect was blocked 63 by propranolol or by the β2-antagonist ICI 118 551 . However, acebutolol, a selective β1-antagonist failed to antagonize the effect of isoprenaline. This negative Fig. 3—Possible influences of the efferent vagal input upon the effect was confirmed by administration of prenaterol synaptic transmission to the gastric muscle within the enteric nervous system. Explanations: A – excitatory (open circle) vagal (β1-agonist) while the ritodrine (β2-agonist) mimicked input (extrinsic neuron, EN) to the excitatory interneuron (IN) the isoprenaline effect. connected with the stimulatory motor neuron (MN) producing Among the other gastrointestinal mechanisms final stimulatory response (+) ; B – excitatory vagal input to the inhibitory interneuron (closed circle) linked with the stimulatory controlling the MMC, serotonin (5-hydroxytryptamine, motor neuron producing final inhibitory response (–); 5-HT) and 5-HT receptors seem to play a pivotal role. C – excitatory vagal input to the excitatory interneuron linked 5-HT is an important central neurotransmitter and the with the inhibitory motor neuron producing final inhibitory gastrointestinal mediator released in the gut from response; D – excitatory vagal input to the inhibitory interneuron enterochromaffin cells64. Among the numerous 5-HT linked with the inhibitory motor neuron producing final stimulatory response receptor subtypes, 5-HT1P, 5-HT3 and 5-HT4 receptor ROMAŃSKI: MIGRATING MOTOR COMPLEX IN BIOLOGICAL SCIENCES 235

subtypes seem to be active in the control of the cooperates with in the induction of phase III gastrointestinal motility65,66. 5-HT induces phase III in in the gastroduodenal region. It was found that motilin man, rat and sheep but it is uncertain whether the receptors in antrum are present principally in nerves same effect occurs in dog since 5-HT did not change and motilin is released or acts via M1 cholinergic the MMC cycles but increased motor activity only67,68. receptors localized on neurons82,83. Therefore, motilin Therefore, the role of serotoninergic neurons in the is the principal hormone initiating phase III of the control of the MMC has not yet been precisely MMC. defined. (PP) is another natural Nitric oxide is the omnipresent regulatory regulatory substance possibly involved in the control substance contributing in many functions in the body of the MMC. Plasma PP level fluctuates in concert 70,71 including central and peripheral nervous system . It with the MMC cycle reaching its apogeum during also functions as the recognized modulator in the phase II or phase III25,84. However, the effect of PP on enteric nervous system and seems to play a role not interdigestive motility is not established since the only in the modulation of sphincter function but also controversial results were presented by different in the control of the gastrointestinal interdigestive authors. Either strong stimulation of the MMC 72 motility . Administration of the inhibitor of the nitric frequency in dogs and pigs by PP or inhibition in dogs oxide synthase, N-nitro-L-arginine methyl ester (L- was reported85. Further studies showed that PP NAME) stimulated the frequency of cyclic motor inhibits the MMC cycle and the interdigestive activity in the rabbit stomach and small bowel in motility86 and it appears that PP can be motilin 73 vitro . Thus the role of nitric oxide in the control of antagonist, at least in part. Action of PP is mediated MMC is rather evident. by cholinergic system221. Thus the role of PP in the The other intrinsic mechanisms controlling the control of the MMC seems to be marked although is MMC cycle involve the naturally occurring peptide still incompletely recognized. modulators acting within the enteric nervous system. Somatostatin is another hormone released into the First comprise mainly opioid receptor-dependent blood circulation in accordance with the MMC cycle influences. The regulatory role of opioid peptides 85,87 74 at least in the dog or some other animal species . In upon the MMC is possible and even very probable man, the results are inconsistent. Tomita et al.88 since the actions of their exogenous derivatives like showed that plasma somatostatin concentration was morphine, loperamide or dermorphin is the most significantly higher during phases III and II than evident and was further confirmed by administration 75,76 during phase I of the MMC in at least 8 hour fasted of naloxone . Naloxone (μ-receptor blocker) given subjects while Näslund et al.89 observed the increase separately during the interdigestive state in the dog 77 in intraduodenal but not in plasma concentration of delayed the occurrence of phase III of the MMC . somatostatin before phase III of the interdigestive Morphine, loperamide, dermorphine or trimebutine cycle. Direct somatostatin contribution in the can induce the MMC pattern and inhibit the fed 75-78 regulation of the MMC cycle seems to be different in pattern . the stomach and small intestine. In the stomach, Hormonal factors affecting the MMC—Several somatostatin or its long-acting analogue, octreotide, hormones can affect the MMC but motilin, pancreatic inhibits motor and myoelectric activty thus polypeptide, and somatostatin are included to the suppressing also the MMC cycle90,91. In the small most specific hormones in this area. intestine, somatostatin shortens the MMC cycle at the Motilin and other compounds involving motilin expense of its phase II and along with its analogue, receptors seem to play an important role in the octreotide, induces the premature phase III-like initiation of phase III of the MMC in man and dog but activity. Thus, it is evident that the role of not in pig79,80. The hormone fluctuates in accordance somatostatin in the control of MMC cycles is with the MMC phases. Discovery of motilin receptors significant. localized on the smooth muscle supported the Several other neurohormonal factors affecting the hypothesis that motilin induces phase III directly. MMC can be listed including the neurally-mediated Later studies in man showed that motilin can induce actions of , CCK, neurotensin, insulin, VIP, phase III only in antrum81. Further studies provided substance P, neurokinin A and galanin4,92-96. They can novel arguments like that the enteric nervous system induce either stimulatory but mostly inhibitory 236 INDIAN J EXP BIOL, APRIL 2009

changes and it is often the case that the same Relationship between gastrointestinal immune substance can evoke the opposite effect depending on system and gastrointestinal motility with special the animal species, dose and the other factors among emphasis upon MMC cycle—Presence of distinct which the release of other regulatory substances is the leukotriene receptors in the smooth muscle cells most important. Such effects are also possible owing represents one of the basic relationships between the to the recognized synaptic coexistence of some gastrointestinal immune system and gastrointestinal modulators with the principal mediator and due to the motility100. There is an increasing number of different neuronal pathways transmitting the stimulus substances linked with the gastrointestinal immune from the so-called first neuron to the smooth muscle. system and affecting the gastrointestinal motility Figure 3 explains why the same substance interacting including ketotifen (mast cell stabilizer)101, with the peripheral nervous system can evoke immunoglobulin G102, platelet activating factor or different effects upon the MMC. Furthermore, leukotrienes103. Some of these substances like 104 interconnections between the intramural ganglia prostaglandin E2 or pranlukast, a leukotriene forming the net of the enteric nervous system increase receptor antagonist105 also affect the interdigestive the possibility not only for different responses to the motility. given stimulus but also for coordination of the These actions are mainly inhibitory since gastrointestinal motility that is clearly observable in prostaglandin E2, the main arachidonic acid the case of the MMC. However, their precise metabolite synthesized in the pathway controlled by mechanisms of action upon the MMC remain to be leukotrienes, can inhibit MMC and reduce elucidated. Table 4 demonstrates the representative intraluminal pressure. Similar effect was observed examples of the endogenous and exogenous after aspirine106. Pranlukast prolongs MMC cycle substances inducing phase III of the MMC in the duration dose-dependently and suppresses the stomach and small intestine. Among them the newly postprandial motility index. Central effect of discovered peptides as ghrelin97, xenin98, and orexin cytokines on gastrointestinal motor activity was also A99 can induce phase III from the small bowel. described107. These findings may help in better

Table 4 ⎯ Peptide and non-peptide regulatory compounds initiating phase III of the MMC from the stomach and small intestine.

Peptide compound Animal species Ref. Non-peptide compound Animal species Ref.

EGF sheep 146 Atropine dog 93,147 Ghrelin man 97 Bethanechol dog 148 Insulin dog 149 Cisapride* man 150 Motilin dog 149 Cisapride** man 18 Octreotide dog 91 Clarithromycin man 151 Orexin rat 99 Clonidine man 93 PP pig, dog 4 Dermorphin rat 75 PYY rat 152 Dobutamine sheep 153 Somatostatin man, pig Dopamine man 154 dog 4 Erythromycin pig, dog 155,156 Substance P dog 4 Hexamethonium dog 157 Xenin man 98 Intraduodenal HCl man 158 Isoproterenol dog 62 LPS sheep 159 Mitemcinal rh. monkey 160 Morphine dog 158 L-NNA man 159 EM 523 dog 160 Oleandomycin dog 156 Pirenzepine dog 147 Serotonin sheep 68 Sumatriptan man 164 Trimebutine dog 165 TTX dog 40 Xylocaine dog 157 * Inconsistent data; ** Stationary phase III ROMAŃSKI: MIGRATING MOTOR COMPLEX IN BIOLOGICAL SCIENCES 237

understanding the pathogenesis of some diseases reported114. Furthermore, the fasting pattern can involving the disturbances of the immune system and persist after feeding, and sometimes the hypertonic motility, including food protein-induced anaphylaxis, phase III of the MMC was observed. During severe cystic fibrosis, inflammatory bowel disease, chronic dyspepsia the absence of phase III was scleroderma, rejections of small bowel allografts, and denoted and during phase II more frequent phasic and perhaps also Crohn’s disease102,103,108-111. tonic contractions occurred115. Absence of phase III or Utility of the animal motility models in human its reduction and increased phase II activity are medicine—Many studies on MMC control present in some patients in the so-called functional mechanisms have been performed, but still a lot of dyspepsia in which no gastric ulceration or any uncertainty remains. Many of these studies utilized features of previous peptic lesions were observed the animal models. Dog seems to be the most (non-ulcer dyspepsia)116. In dyspeptic patients without common model applicable for the MMC study but gastric ulcers but with Helicobacter pylori positive considering the present limitations (ethics, costs etc.), gastritis, lack of phase III and abnormalities present other models like rat or mouse as the new models during phase II of the MMC were reversed by acceptable for man are necessary. In spite of Helicobacter pylori eradication117,118. Impaired antral substantial objections concerning the different motility is the most common feature of functional structure of the stomach, different digestive processes dyspepsia119. and metabolism, sheep seem to be also applicable as MMC in gastroparesis—Term “gastroparesis” is the model for the study of antral and small intestinal reserved for the group of principal gastric motility motility including the MMC. The differences between disturbances caused by surgical procedures and is the man and sheep does not seem to be greater unless consequence of the neuropathies including diabetic they are smaller than between man and rodents in this neuropathy. Thus, it is the most frequently linked with scope. Thus, the ovine model does not appear to be the diabetes mellitus whereas diabetic gastroparesis is much different from the hog model and is much more the most common form of this disease120. Delayed feasible to apply. The increasing knowledge on MMC gastric emptying in the absence of its mechanical cycle and its control mechanisms resulting from the obstruction may represent its good although rather enormous number of studies, that involved the human general definition. Thus, during gastroparesis various and animal models, facilitates the diagnosis of several motility disturbances may occur either in the stomach MMC disturbances and facilitates the development of or in the small intestine. These changes also comprise the pharmacological tools for their treatment. the interdigestive period. Gastric phase III can be

suppressed or abolished and intestinal motor pattern MMC alterations in gastrointestinal diseases 114,121,122 Among the variety of available techniques used for can be abnormal as well . assessing the gastrointestinal motility, either water- The and MMC—The perfused or strain gauge-manometric technique irritable bowel syndrome (IBS) represents another appears to be the most suitable for the interdigestive group of severe gastrointestinal perturbations and 116,123 motility recording in humans112,113. The same these changes are not easily comparable . The techniques are applicable in the animals especially if gastrointestinal symptoms and motility changes occur the possibility of the use of more invasive techniques exclusively during the wakefulness and comprise the is impeded. Manometry in man and electromyography irregular MMC cycles as well as shorter duration of in animals allow to perform the long-term recording MMC interruption after a meal. Sometimes abnormal and to obtain the most precise recordings. Using these MMCs occur also during the day. Two sub- techniques several alterations of the interdigestive syndromes of IBS can be distinguished: diarrhea- motility have been recognized. predominant and constipation-predominant syndrome. MMC in dyspepsia—Dyspepsia is the clinical Both sub-syndromes differ with the character of syndrome accompanying in many cases of the motility alterations. Diarrhea-predominant patients interdigestive gastrointestinal motor disorders, and exhibit the increased frequency of the MMC cycles occurring more frequently in the stomach than in the although often it is still normal. The amplitude of small bowel. During idiopathic dyspepsia the decrease contractions during phase III is higher while shorter of the intensity of antral pressure waves as well as the duration and slower propagation velocity are observed 123 diminished antral response to feeding were in constipation-predominant IBS . There is greater 238 INDIAN J EXP BIOL, APRIL 2009

incidence of the atypical motor patterns during phase several other phase III anomalies have been II (rapidly propagated bursts of contractions) than in described114. Further, after surgery and during various constipation-predominant IBS. However, plasma systemic and gastrointestinal diseases numerous motilin concentration is enhanced in both groups of disturbances of the whole MMC and/or its phases patients either during the interdigestive or during the have been reported. Most of them are listed in digestive state124. In patients with IBS, during which Table 5. As it can be derived from these data, possible the decreased frequency and duration of phase III was MMC disturbances are confined to the relatively observed, small-intestinal bacterial overgrowth was small their number and in the given illness they can found125. Its eradication normalized the motor activity occur in various combinations. It is possible that in part. similar MMC disturbances occur in different diseases. MMC abnormalities in other diseases—Apart from The substantial part of the listed diseases are the disturbances of phase III activity discussed above, idiopathic and intractable; even the effective

Table 5—Disturbances of the MMC and its phases in the stomach and small intestine in gastrointestinal diseases. Disease Species M M C disturbance Ref. Abdominal γ irradiation rat Reduced MMC frequency followed by its marked disruption 166 Achalasia man Loss of cyclic MMCs, prolonged and suppressed phase II, disturbed 167 aboral migration of phase III Acute pancreatitis rat Prolonged MMC cycles, disturbed MMC in the jejunum, bacterial 127 overgrowth Bacterial overgrowth man Attenuated MMC activity (presumed cause and consequence) 168 Carcinoid tumors* man Increased migration velocity oh phase III, increased cyclic frequency of 114 the MMC Cholecystitis man Absence of phase III (partial), lower amplitude of phase III 169 Chronic intestinal man Suppression of interdigestive motor activity, MMC cycles preserved, 170 pseudoobstruction persistence of fasting pattern after a meal 171 Constipation man Absence of phase III, continuous irregular pattern, decreased amplitude 172 of contractions Diabetes man Absent or abnormal phase III (retrograde or stationary) 173 Diabetes man Prolonged MMC cycles due to prolonged phase II, decreased incidence 174 or lack of gastric phase III Dumping syndrome man Lack of phase III, lowered plasma motilin and somatostatin 88 concentration E. coli enterotoxin pig Prolonged MMC cycle due to prolonged phase II, increased migration 175 velocity of phase III Experimental diabetes dog, sheep Continuous sequence of MMC regardless of feeding conditions, mellitus decreased MMC cycle incidence, decreased recurrence and intensity of the MMC Exp. hyperthyroidism dog Increased contraction frequency during phase II, MMC cycles 177 preserved Exp. jejunal inflamm. Rat Loss of phase I quiescence, prolonged MMC cycles, non-propagated 111 activity fronts Exp. mechan. obstruct. Rat Loss of MMCs below obstruction 177 Gallstones man Longer MMC cycles due to prolonged phase I, enhanced plasma 178 motilin concentration Gastroduodenal ulcer man Stomach: decreased occurrence of phase III, shortened phase II; small 114 bowel: prolonged phase II Man Suppressed antral phase II activity, ectopic phases III 179 rat, dog Rats: MMC cycles replaced by fed-like pattern; dogs: decreased MMC 180 frequency Hyperinsulinemia man Lack of phase III in antrum; retropropagated phase III in the duodenum 180 Idiopath. gastric stases man Retrograde propagation of phase III-like activity 114 Myotonic dystrophy man Interrupted phase III of the MMC 114 Systemic sclerosis man Absence of MMC cycles, suppressed the interdigestive motility index 181 man Abnormal phase III 182 Thyrotoxicosis man Increase in migration velocity of phase III 114 *Increased serotonin secretion ROMAŃSKI: MIGRATING MOTOR COMPLEX IN BIOLOGICAL SCIENCES 239

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