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Keywords:

  • colon;
  • constipation;
  • ileum;
  • naloxone;
  • opioid-receptor;
  • peristalsis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References

Gastrointestinal motility can be assessed in vitro by investigating the effects of drugs or gene knockouts on intestinal propulsion, and on neurone-mediated responses evoked by electrical field stimulation (EFS). The latter predominantly measure enteric motor activity and can detect prokinetic activity of exogenous agents. Some evidence suggests that naloxone has prokinetic activity when evaluated for an ability to modulate responses to EFS, but the effects are inconsistent across different species or intestinal regions. Models of intestinal peristalsis measure an integrated sensory-motor nerve function and possess more intact neuro-neuronal connections. In such preparations, the effects of naloxone also suggest a prokinetic property but again, this is inconsistent. By contrast, consistent prokinetic activity of naloxone is apparent in models where peristalsis is compromised by drug-induced suppression of motor nerve activity or by modulation of endogenous processes using receptor antagonists or inappropriate intraluminal distension. These data suggest that endogenous opioids play little or no role in normal intestinal physiology, but suppress intestinal motility when motor function is compromised. Consequently, drugs that antagonize opioid receptors may exert prokinetic activity in conditions where intestinal motility is reduced, such as constipation. Further work is required to elucidate the opiate receptor(s) involved.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References

The actions of exogenous opioid receptor agonists on gastrointestinal (GI) physiology have been studied extensively.1 Less is known about the roles of endogenous opioids on GI physiology. This review follows on from a previous study2 by focusing on the role of endogenous opioids in GI motility. For this purpose, data derived mainly from experiments with isolated GI preparations, where enteric nerve functions can be more precisely modelled, have been used. Such technologies are highly flexible. Difficult pathological conditions can be created, imperfect ligands (e.g. non-selective, poorly bioavailable or in scarce supply), and differences between species (including man), can be studied and, provided standard in vivo behaviours and drug efficacy are reproduced, the data gathered can be used to predict functions and facilitate in vivo study design.

Models

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References

There are many methods of modelling GI functions in vitro. Among the most common are those that examine nerve-mediated responses of muscle strips, evoked by electrical currents [e.g. electrical field stimulation (EFS)] or neuronal stimulants (e.g. nicotine) and those that examine reflex functions in more intact preparations of the gut (e.g. peristalsis or accommodation).

Electrical field stimulation  Responses evoked by EFS involve different motor nerve phenotypes, so the net effect depends on the species, the gut region/muscle layer and the parameters of EFS. It is important to understand how such variations affect responses to opioid receptor agonists and antagonists, to draw appropriate conclusions. Figure 1 shows an example using isolated human taenia coli. In this preparation, EFS usually evokes an atropine-sensitive contraction, followed by a marked ‘after contraction’ on termination of the stimulus. Atropine (a muscarinic receptor antagonist) prevented the initial contraction revealing an ability of EFS to evoke muscle relaxation, which is thought to be mediated predominantly through the release of nitric oxide.3 Atropine also partly reduced the amplitude of the ‘after contraction’, the remaining contraction being mediated through the release of tachykinins.4 This complex pharmacology allows detection of the actions of exogenously applied substances on cholinergic, tachykinergic (excitatory) and nitrergic (inhibitory) motor functions, and detection of any direct action on muscle tension.

image

Figure 1. Illustration of responses to electrical field stimulation (EFS) in human isolated sigmoid taenia coli. In this example, EFS (horizontal bar) was applied for 30 s using bipolar square-wave pulses of 0.5 ms width and maximally effective voltage. All responses were prevented by tetrodotoxin 1–3 µmol L−1; n = 3. During EFS, in the absence of atropine, a rapid contraction occurred in 3/4 preparations, equivalent to 55% (range 31–58%) of the larger ‘after contractions’ that followed termination of EFS.

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An excellent example of how this technology helps explain the actions of opioid receptor ligands is reported in the experiments of Angel et al. [4]. EFS was used to evoke neurone-mediated responses in longitudinal and circular muscle preparations of human descending colon. Activation of δ-opioid receptors by methionine enkephalin or [d-penicillamine2, d-penicillamine5]-enkephalin (DPDPE), and activation of κ-opioid receptors by dynorphin or trans-3,4-dichloro-N-methyl-N-(2-[1-pyrolidinyl]-cyclohexyl) (U-50488H), decreased both the initial and the ‘after contractions’ evoked by EFS; the former are atropine-sensitive and the latter are abolished by a combination of atropine and substance P desensitization.

Not detected in these experiments, possibly because of the dominance of the excitatory neurotransmission, is a reported ability of δ-opioid receptor activation to inhibit non-adrenergic, non-cholinergic inhibitory neuromuscular transmission in the circular muscle of the colon.5 It has also been found that low concentrations of the µ-opioid receptor agonist, [D-Ala2, n-Me-Phe4, Gly5,-ol]-enkephalin reduced the amplitude of the relaxation observed in circular muscle preparations during EFS, and tended to decrease and increase the amplitude of the initial contraction in longitudinal and circular muscle, respectively.4 These data suggest an ability of δ- and κ-opiate receptors to interact with both cholinergic and tachykinergic functions, with µ-receptors tending to interact more effectively with the inhibitory motor system and, to a lesser extent, cholinergic function. The latter is consistent with the ability of the µ-opiate receptor agonist, morphine, to reduce acetylcholine release from electrically stimulated preparations of isolated human taenia coli6 and reduce nitric oxide release from inhibitory enteric neurones in circular, but not longitudinal, muscle preparations of guinea-pig ileum.7

Interestingly, naloxone 0.1 µmol L−1 or 1 µmol L−1 also tended to reduce the initial, cholinergically mediated contractions to EFS in both longitudinal and circular muscle preparations,4 although this was only significant statistically in the circular muscle using the 1 µmol L−1 concentration. This apparently conflicting result illustrates the ease with which a potentially misleading conclusion can be drawn from such experiments. Thus, as discussed by the authors, there is a clear possibility that naloxone indirectly reduced the effect of excitatory neurotransmision simply by removing the ability of endogenous opioids to suppress the action of a dominant inhibitory neurotransmitter. Further experiments are therefore required to re-examine the effects of naloxone in the presence of inhibitors of the different neurotransmitter functions. Nevertheless, these data represented the first time that a role for endogenous opioids in human intestinal motility had been demonstrated using isolated preparations of the intestine.

The finding that the opioid receptor agonists were not able to directly affect human colonic muscle tension4 was in agreement with an earlier study using morphine and isolated human ileum.8 However, the ability of morphine to evoke non-propulsive, atropine-sensitive contractions in the terminal ileum in healthy volunteers was also reported. This suggests that if EFS had been applied to the isolated ileum, similar to that described above, a facilitation of cholinergically mediated contractions would have been observed.

Propulsive movement  Responses evoked by EFS predominantly reflect motor neurone activity and not necessarily those driven by the sensory or intrinsic primary afferent neurones of the enteric nervous system. Consequently, measurement of peristalsis is a valuable additional technique, as the reflex involves both sensory and motor nerve activity. Methods of evoking peristalsis are well described, especially using guinea-pig ileum. Colonic motility is more complex and has been studied in vitro by measuring migrating motor complexes, the transit of balloons, artificial9 or endogenous10 faecal pellets and techniques that measure movements occurring spontaneously or evoked by electrical stimulation or intraluminal distension in ‘obstructed’ or ‘open’ preparations of colon where the intraluminal content can flow freely in response to intraluminal distension. Individual components of the propulsive reflex have also been assessed by recording ascending/descending movements evoked by different methods, including electrical stimulation11 and muscle stretch.12

The advantages of using models of peristalsis are well illustrated by a number of studies.13,14 Morphine, and other ligands active at the µ-opioid receptor, failed to affect contractions evoked by EFS in rat jejunum or ileum. However, when applied serosally to a model of peristalsis in rat ileum, an inhibitory response mediated through µ-opiate receptors was clearly visible. It was suggested that these data could be explained by morphine interacting with neuronal structures proximal to the cholinergic motor neurone,14 such as an inhibitory motor neurone/interneurone or intrinsic primary afferent neurone.

Ligands, oligonucleotides and knockout mice

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References

Understanding the roles of endogenous opioids is dependent on the use of selective opioid receptor antagonists, and an update on progress in identifying such antagonists is available.15 However, to date most studies have used naloxone, an antagonist with poor selectivity for the different opioid receptors (e.g. inhibition constant [Ki] values for the human µ-, κ- and δ-opiate receptors are 3.3, 8.1 and 33.0 nmol L−1, respectively).16 It is therefore often difficult to interpret the effects of naloxone in terms of any selective activity at each of the opioid receptors.

Antisense oligonucleotides to µ- and δ-opioid receptor mRNA17 and opioid peptide, or receptor, knockout mice18 have been used to make additional predictions on the functions of endogenous opioids. However, caution is required. While treatment with the antisense oligonucleotides did not significantly change normal rat GI motility (assessed using a charcoal meal) the investigators caution that, after treatment, residual functional opioid receptors can remain active. In µ-opioid receptor knockout mice, the ability of morphine to slow intestinal transit of a charcoal meal was absent. However, when compared with the wild-type mice, the normal rate of GI transit was reduced by approximately 35%.19 These animals did not exhibit any apparent up-regulation of δ- or κ-opioid receptor function, and the investigators suggested that the removal of the µ-opioid receptor gene must have upregulated a separate mechanism to ‘compensate’ for the suppressive role normally mediated through the µ-opioid receptor. If this suggestion is correct, it does not explain why there is a need to create a level of suppression that is greater than in the wild-type mice. Thus, although the fundamental reason for using these mice remains attractive, considerable care needs to be exercised when interpreting the data generated.

Species

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References

The need to recognize cross-species variations is critical. For example, µ- and κ-opioid receptors are able to suppress cholinergic function in guinea-pig ileum, and there is a need to activate δ-opioid receptors and, to a lesser extent, µ-receptors to exert similar activity in rat small intestine.13,14 An ability of µ-opioid receptor agonists to cause direct muscle contraction of dog small intestine and induce diarrhoea instead of constipation2 makes the dog an atypical species relative to many others, including humans. Such variations mean that extreme care must be taken when making cross-species comparisons. It is not yet clear which species models most closely the biology of the human intestine.

Stomach  Naloxone had no effects on vagal nerve-evoked, cholinergically mediated contractions in isolated rat oesophagus20 or on acetylcholine release21 and non-adrenergic, non-cholinergic inhibitory responses11 evoked in isolated rat stomach by vagal nerve stimulation or EFS, respectively. Each of these responses was sensitive to inhibition by µ-opioid receptor agonists. In vivo, naloxone may have variable effects on gastric motility in humans to facilitate sensitivity to emesis by removing an endogenous opioid suppression of this reflex22 and has been reported to modulate vagal nerve-mediated changes in gastric motility in anaesthetized cats.23 These studies suggest that further work is required before the effects of opioid receptor antagonism on gastric pathophysiology are properly understood.

Intestine  A suppressant effect of endogenous opioids can be detected by the use of opioid receptor antagonists, which enhance responses to electrical nerve stimulation in several isolated intestinal preparations, including the human colon (Table 1). In most examples, further experiments are now required using selective receptor antagonists to determine which receptors are involved. However, while these data are an exciting indication that endogenous opioids can play a role in intestinal motility, the inconsistency of effects across different models and species suggests that it is necessary to use different models of motility to detect the true function of endogenous opioids.

Table 1.  Effects of opioid receptor antagonism on neurotransmitter release or function in isolated intestinal preparations
Response observedSpecies and region of intestineReceptor antagonist
  1. ACH, acetylcholine; EC50, median effective concentration; EFS, electrical field stimulation. *An ability of naloxone to exert this depressive action through facilitation of simultaneous release of inhibitory neurotransmitter was not examined in these experiments, although the possibility that this opposing action could explain the overall suppressive action of naloxone was discussed by the authors.

[UPWARDS ARROW] Release of ACH evoked by electrical nerve stimulation48Guinea-pig ileumNaloxone
[UPWARDS ARROW] Release of substance P during intraluminal distension49Guinea-pig ileumNaloxone 1.5 µmol L−1
No change in neurone-mediated contractions evoked by high-frequency (10 Hz) EFS50Guinea-pig ileum longitudinal muscleNaloxone
[UPWARDS ARROW] Release of ACH evoked by electrical nerve stimulation51Guinea-pig colonCyprodime (µ-receptor antagonist; EC50 4.5 nmol L−1) or nor-binaltorphimine (κ-receptor antagonist; EC50 0.33 nmol L−1)
[UPWARDS ARROW] Release of inhibitory transmitter at inhibitory motor nerve terminals52Dog duodenal circular muscleNaloxone
[UPWARDS ARROW] Neurone-mediated contractions evoked by EFS13Rat jejunum longitudinal muscleNaloxone 0.1 µmol L−1 and 1 µmol L−1
[DOWNWARDS ARROW] Cholinergically mediated contractions evoked by EFS4*Human colon circular muscleNaloxone 0.1 µmol L−1 and 1.0 µmol L−1 (statistically significant at 1 µmol L−1 only)
Tendency to [DOWNWARDS ARROW] cholinergically mediated contractions evoked by EFS4*Human colon longitudinal muscleNaloxone 0.1 µmol L−1 and 1.0 µmol L−1 (not statistically significant)
No change in release of ACH evoked by electrical nerve stimulation6Human sigmoid taenia coliNaloxone 1.1 µmol L−1

Intestinal peristalsis and propulsion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References

Evidence to suggest that endogenous opioids exert a suppressive function on normal patterns of intestinal motility has also been observed in animal models of peristalsis, mainly using the ileum. Naloxone-enhanced peristaltic activity was evoked by intraluminal distension in isolated guinea-pig duodenum, jejunum, ileum and rectum,24–29 the effects being least in the duodenum and rectum.27 Similar activity was observed using more selective antagonists at the µ- (cyprodime) and κ- (nor-binaltorphimine) opioid receptors; antagonism at the δ-opioid receptor had no effect.30 Naloxone 0.2–0.4 µmol L−1 also facilitated peristalsis in isolated rabbit, cat and rat ileum.14,31 Consistent with these observations, the cyclic somatostatin analogue and µ-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), facilitated an ascending excitatory pathway evoked by EFS in rat ileum; antagonists at the κ- or δ-opioid receptors had no effect.32

Together, these data also find some consistency with studies in conscious rats. Although naloxone had no significant effects on stomach-to-caecum transit times measured using a breath–hydrogen technique, there was a tendency for the drug to increase the amount of meal transported into the caecum when measured by radiolabelling the same meal.33 In studies using flat sections of guinea-pig colon, naloxone 1 µmol L−1 and 10 µmol L−1 were found to increase the descending relaxation (plus vasoactive intestinal peptide release) and ascending contraction reflexes evoked by radial stretch.34 However, when using more intact preparations, naloxone 0.1 µmol L−1 had no effect on the movements of endogenous faecal pellets in guinea-pig mid-to-distal colon10 and naloxone 0.5 µmol L−1 had no effects on the peristaltic reflex in rat proximal colon (BR Tuladhar, unpublished).

A study has shown that the release of methionine enkephalin from guinea-pig ileum was reduced during peristalsis.35 Peristalsis is not usually sustained during prolonged intraluminal distension, and is interspersed by periods of inactivity; methionine enkephalin release is significantly increased during these inactive periods.35 It is argued that these data support the hypothesis that endogenous opioids act to suppress intestinal motility, by suggesting that this function plays a greater role when required, as part of an intestinal defence against the ‘over-activity’ created by prolonged intestinal distension or other stimuli. Such a possibility is consistent with the ability of naloxone to reduce the intermittent periods of peristaltic inactivity observed during prolonged periods of distension.24–26 If this hypothesis is correct, then drugs that prevent the actions of endogenous opioids are more likely to exert intestinal prokinetic activity during conditions associated with reduced colonic motility, than simply increase the efficiency of the reflex itself26 provided the immobility is not extreme (e.g. during conditions of obstruction leading to exhaustion).2,27

Impaired intestinal propulsion and peristalsis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References

Various experiments report the ability of low concentrations of naloxone to ‘rescue’ peristalsis during conditions when peristaltic efficiency is impaired. This effect may occur even in preparations where naloxone alone has previously showed no ability to affect ‘normal’ propulsive activity. For example, in isolated guinea-pig colon, naloxone did not affect the propulsive reflex, as measured by timing the rate at which endogenous faecal pellets were expelled spontaneously from the colon.10 However, after the expulsion of these pellets was reduced by granisetron (a selective 5-hydroxytryptamine type 3 receptor antagonist), morphine or clonidine (a selective α-2 adrenoceptor agonist), naloxone 0.1 µmol L−1 prevented or greatly reduced each of these inhibitory actions (Fig. 2). These data suggest that the ability of endogenous opioids to play a suppressive role in colonic motility is more apparent when peristalsis is impaired. Furthermore, the prokinetic function of naloxone is independent of the pharmacological method of impairment or the use of ligands that directly (morphine, clonidine) or indirectly (granisetron) modulate colonic motility. These conclusions are consistent with those from similar experiments that showed that naloxone 0.5 µmol L−1 could reverse the inhibition of peristalsis in guinea-pig small intestine caused by purinergic receptor ligands, haloperidol, atropine or hexamethonium.24,29,36

image

Figure 2. Reversal by naloxone of impaired propulsive activity in isolated guinea-pig colon.10 Mid-to-distal colon containing endogenous faecal pellets was secured in horizontal organ baths with Krebs' solution perfused through the chamber at a constant rate (bubbled with 5% CO2 in O2, and maintained at 37 °C). The time taken for each pellet to be expelled spontaneously in an anal direction was measured. After consistent control readings were obtained, granisetron, morphine or clonidine was added to the bathing solution and the effects monitored for 60 min. The bathing solution was then exchanged for a fresh solution containing the same compound plus naloxone 0.1 µmol L−1 (n = 6 minimum).

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To determine if this type of colonic prokinetic-like activity of naloxone can be detected in a species other than guinea pig, the peristaltic activity in mouse colon was investigated using the method described by Tuladhar & Naylor37(Fig. 3). This design incorporated an ability to measure both the changes in intraluminal pressures and the productive work performed by the colon, in terms of the fluid propelled from the open colon during muscle activity. Peristalsis was evoked by raising the intraluminal pressure to 4–6 cm H2O using Krebs’ solution. Consequently, the proximal colon was used, where intraluminal contents are normally semi-solid, as opposed to the more distal regions of the colon where relatively firm faecal pellets are found.

image

Figure 3. Apparatus for inducing and measuring the peristaltic reflex in isolated mouse colon.37

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The average volume ejected per peristaltic stroke was 0.46 mL, the rate of peristalsis was 31.5 strokes hour−1 and the velocity of migration of peristaltic contractions in the anal direction was 4.3 cm min−1. Morphine reduced the volume ejected and the rate of peristalsis in a concentration-dependent manner (Fig. 4), with abolition of peristalsis in all tissue at 3 µmol L−1. The resting tone of the tissues was also increased by morphine (possibly reflecting a suppression of nitric oxide release).7 Smaller, more frequent contractions of the circular muscles were also observed (Fig. 4), these being non-productive, as judged by the absence of fluid expulsion. Addition of naloxone 0.5 µmol L−1 reversed the effects of morphine and coordinated, anally directed contractions were restored in all tissues tested (Fig. 4).

image

Figure 4. Inhibition of peristalsis in isolated mouse colon by morphine and its reversal by naloxone. The experiment was conducted as described by Tuladhar & Naylor.37 After obtaining consistent peristaltic movements, increasing concentrations of morphine were added to the serosal bathing solution, followed by naloxone at the concentrations indicated. This concentration of naloxone had no effect on any measured parameter of peristalsis when administered on its own. The volume expelled during each peristaltic movement was determined by calibration against the change in pressure induced by 0.3 mL toward the transducer.

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Similar experiments were performed using a submaximally effective concentration of clonidine instead of morphine. In these experiments, naloxone (0.5 µmol L−1) reduced, but did not abolish, the inhibitory effect of clonidine (Fig. 5A illustrates the volume of fluid ejected per stroke of peristalsis and (B) is the rate of peristalsis). The experiments with isolated mouse colon are therefore consistent with the concept that endogenous opioids exert a restraining influence on the intestine, the effects being most apparent during conditions of impaired colonic motility. It is possible that this effect of endogenous opioids is limited to colonic motility and does not extend to the defecation reflex itself. Indeed, it has been reported that intracerebroventricular naloxone or subcutaneous naloxonazine (µ-selective) had no effect on bead expulsion by conscious mice.38 However, validation experiments are required in the latter study.

image

Figure 5. Inhibition of peristalsis in isolated mouse colon by clonidine and its partial reversal by naloxone. The experiment was conducted as described by Tuladhar & Naylor.37 After obtaining consistent peristaltic movements in preparations incubated with either naloxone 0.5 µmol L−1 or vehicle, a submaximally effective concentration of clonidine (3 nmol L−1) was added to the serosal bathing solution and the effects monitored for 15 min. Data are expressed as the mean ± SEM for (A) the volume of fluid ejected per stroke of peristalsis and (B) the rate of peristalsis. *P < 0.05.

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The suggestion that endogenous opioids act to suppress intestinal motility as part of a ‘defensive’ mechanism against inappropriate or adverse conditions is supported by different studies in conscious rats, and also by studies in humans. In rats, naloxone only slightly increased normal stomach-to-caecum transit times; but when transit was slowed by ileal infusion of lipids, naloxone abolished this delay.33 These experiments suggest that endogenous opioids contribute to the mechanism of the ‘ileal brake’, either directly or indirectly, through a modulation of the effects exerted on the enteric nervous system by mechanisms extrinsic to this system. Similarly, in healthy human volunteers, naloxone may not affect intestinal motility.39 Other studies, however, suggest that naloxone inhibits the delay in small intestinal transit, but not gastric emptying,40 caused by the inclusion of triglycerides in the meal.41

In fasted rats, disruption of the migrating myoelectric complex by Escherichia coli endotoxin, but not by platelet activating factor, was reduced by naloxone.42 Also in rats, naloxone had no effect on the delay in GI transit (measured by a liquid dye marker administered orally) caused by abdominal skin incision or by abdominal laparotomy, but inhibited the delay in transit measured after abdominal laparotomy plus manipulation of the small and large intestine.43 Each of these experiments, together with the previously described studies that modelled constipation-like behaviours, is consistent with the reported ability of naloxone to reverse constipation,44 increase faecal wet weights in geriatric patients45 and accelerate colonic transit in normal volunteers.46

Finally, it has been suggested that endogenous opioids play a role in the adaptation response of the intestine to acute stress. In rats, naloxone or methylnaloxone minimized the increases in colonic epithelial ion secretion and permeability observed after longer and more continuous periods of stress.47 Together, all these observations are consistent with a defensive role for GI endogenous opioids.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References

Endogenous opioids may play certain roles in the control of gastric ingestive, digestive and defensive behaviours, but these are currently poorly understood.

If endogenous opioids play a role in normal intestinal motility their role is subtle, and may be important only in defending the intestine against moderate ‘over-activity’, tending to suppress patterns of motility.

Inhibition of the actions of endogenous opioids can exert clear intestinal prokinetic activity during conditions of disrupted motility. This suggests a potential for these agents in the treatment of conditions such as ileus and constipation.

To date, most studies have used naloxone. Further work is now required to establish the opioid receptor(s) involved in the actions of naloxone, especially in the human gut, and to determine if the recently identified ligands (e.g. nociceptin) acting on naloxone-insensitive, opioid-like receptors can also influence GI functions.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Tools: strengths and limitations
  5. Models
  6. Ligands, oligonucleotides and knockout mice
  7. Species
  8. Effects of opioid receptor antagonists
  9. Electrofield stimulation and neurotransmitter release
  10. Intestinal peristalsis and propulsion
  11. Impaired intestinal propulsion and peristalsis
  12. Conclusions
  13. References
  • 1
    Kurz A, Sessler DI. Opioid-induced bowel dysfunction. Pathophysiology and potential new therapies. Drugs 2003; 63: 64971.
  • 2
    Kromer W. Endogenous and exogenous opioids in the control of gastrointestinal motility and secretion. Pharmacol Rev 1988; 40: 12162.
  • 3
    Tomita R, Fujisaki S, Ikeda T, Fukuzawa M. Role of nitric oxide in the colon of patients with slow-transit constipation. Dis Colon Rectum 2002; 45: 593600.DOI: 10.1007/s10350-004-6251-8
  • 4
    Angel F, Chamouard P, Klein A, Martin E. Opioid agonists modulate excitatory and inhibitory neurotransmission in human colon. J Gastrointest Mot 1993; 5: 28997.
  • 5
    Hoyle CHV, Burnstock G, Jass J, Lennard-Jones JE. Enkephalins inhibit non-adrenergic, non-cholinergic neuromuscular transmission in the human colon. Eur J Pharmacol 1986; 131: 15960.DOI: 10.1016/0014-2999(86)90532-7
  • 6
    Burleigh DE, Trout SJ. Morphine attenuates cholinergic nerve activity in human isolated colonic muscle. Br J Pharmacol 1986; 88: 30713.
  • 7
    Lenard L, Halmai V, Bartho L. Morphine contracts the guinea-pig ileal circular muscle by interfering with a nitric oxide mediated tonic inhibition. Digestion 1999; 60: 5626.DOI: 10.1159/000007707
  • 8
    Daniel EE, Sutherland WH, Bogoch A, Kent JT. Effects of morphine and other drugs on motility of the terminal ileum. Gastroenterology 1958; 36: 51023.
  • 9
    Kadowaki M, Wade PR, Gershon MD. Participation of 5-HT3, 5-HT4 and nicotinic receptors in the peristaltic reflex of guinea-pig distal colon. Am J Physiol 1996; 271: G84957.
  • 10
    Sanger GJ, Wardle KA. Constipation evoked by 5-HT3 receptor antagonism: evidence for heterogenous efficacy among different antagonists in guinea-pigs. J Pharm Pharmacol 1994; 46: 66670.
  • 11
    Storr M, Gaffal E, Schusdziarra H-D, Allescher HD. Endomorphins 1 and 2 reduce relaxant non-adrenergic, non-cholinergic neurotransmission in rat gastric fundus. Life Sci 2002; 71: 3839.DOI: 10.1016/S0024-3205(02)01681-8
  • 12
    Spencer NJ, Hennig GW, Smith TK. A rhythmic motor pattern activated by circumferential stretch in guinea-pig distal colon. J Physiol 2002; 5452: 62948.DOI: 10.1113/jphysiol.2002.028647
  • 13
    Coupar IM, De Luca A. Opiate and opiate antidiarrhoeal drug action on rat isolated intestine. J Auton Pharmacol 1994; 14: 6978.
  • 14
    Coupar IM. The peristaltic reflex in the rat ileum. Evidence for functional µ- and δ-opiate receptors. J Pharm Pharmacol 1995; 47: 6436.
  • 15
    Kaczor A, Matosiuk D. Non-peptide opioid receptor ligands − recent advances. Part II. Antagonists. Current Med Chem 2002; 9: 1591603.
  • 16
    Greenwood-Van Meerveld B, Little PJ, DeHaven RN, Gardner CJ, Hicks GA, DeHaven-Hudkins DL. Preclinical studies of opioids and opioid antagonists on gastrointestinal function. Neurogastroenterol Motil 2004; 16(Suppl. 2): 4653.
  • 17
    Pol O, Valle L, Puig MM. Antisense oligonucleotides to µ- and δ-opioid receptor mRNA block the enhanced effects of opioids during intestinal inflammation. Eur J Pharmacol 2001; 428: 12736.DOI: 10.1016/S0014-2999(01)01281-X
  • 18
    Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol 2002; 66: 285306.DOI: 10.1016/S0301-0082(02)00008-4
  • 19
    Roy S, Liu H-C, Loh HH. µ-Opioid receptor-knockout mice. the role of µ-opioid receptor in gastrointestinal transit. Mol Brain Res 1998; 56: 2813.DOI: 10.1016/S0169-328X(98)00051-5
  • 20
    Storr M, Geisler F, Neuhuber WL, Schusdziarra V, Allescher HD. Endomorphin-1 and -2, endogenous ligands for the µ-opioid receptor, inhibit striated and smooth muscle contraction in the rat oesophagus. Neurogastroenterol Motil 2000; 12: 4418.DOI: 10.1046/j.1365-2982.2000.00220.x
  • 21
    Yokotani K, Osumi Y. Involvement of µ-receptor in endogenous opioid peptide-mediated inhibition of acetylcholine release from the rat stomach. Jpn J Pharmacol 1998; 78: 935.DOI: 10.1254/jjp.78.93
  • 22
    Rudd JA, Cheng CHK, Naylor RJ, Ngan MP, Wai MK. Modulation of emesis by fentanyl and opioid receptor antagonists in Suncus murinus (house musk shrew). Eur J Pharmacol 1999; 374: 7784.DOI: 10.1016/S0014-2999(99)00285-X
  • 23
    Okamoto T, Kurahashi K, Fujiwara M. Effects of naloxone and opioid agonists on gastric excitatory responses to stimulation of the vagus nerve in cats. Br J Pharmacol 1988; 95: 32934.
  • 24
    Van Neuten JM, Janssen PAJ, Fontaine J. Unexpected reversal effects of naloxone on the guinea-pig ileum. Life Sci 1976; 18: 80310.DOI: 10.1016/0024-3205(76)90005-9
  • 25
    Kromer W, Pretzlaff W. In vitro evidence for the participation of intestinal opioids in the control of peristalsis in the guinea-pig small intestine. Naunyn-Schmiedeberg's Arch Pharmacol 1979; 309: 1537.
  • 26
    Kromer W, Pretzlaff W, Woinoff R. Opioids modulate periodicity rather than efficacy of peristaltic waves in the guinea-pig ileum in vitro. Life Sci 1980; 26: 185765.DOI: 10.1016/0024-3205(80)90614-1
  • 27
    Kromer W, Pretzlaff W, Woinoff R. Regional distribution of an opioid mechanism in the guinea-pig isolated intestine. J Pharm Pharmacol 1981; 33: 98101.
  • 28
    Kromer W, Schmidt H. Opioids modulate intestinal peristalsis at a site of action additional to that modulating acetylcholine release. J Pharmacol Exp Ther 1982; 223: 2714.
  • 29
    Holzer P, Lippe IT, Heinemann A, Bartho L. Tachykinin NK1 and NK2 receptor-mediated control of peristaltic propulsion in the guinea-pig small intestine in vitro. Neuropharmacology 1998; 37: 1318.DOI: 10.1016/S0028-3908(97)00195-0
  • 30
    Shahbazian A, Heinemann A, Schmidhammer H, Beubler E, Holzer-Petsche U, Holzer P. Involvement of µ- and κ-, but not δ-, opioid receptors in the peristaltic motor depression caused by endogenous and exogenous opioids in the guinea-pig intestine. Br J Pharmacol 2002; 135: 74150.
  • 31
    Kromer W, Pretzlaff W, Scheiblhuber E. In vitro evidence for an involvement of intestinal endorphins in the control of peristalsis in the guinea-pig ileum. Comparison of rabbit, rat, cat and dog small intestine. In: WayEL, ed. Endogenous and Exogenous Opiate Agonists and Antagonists. New York: Pergamon, 1980: 33740.
  • 32
    Allescher HD, Storr M, Brechmann C, Hahn A, Schusdziarra V. Modulatory effect of endogenous and exogenous opioids on the excitatory reflex pathway of the rat ileum. Neuropeptides 2000; 34: 628.DOI: 10.1054/npep.1999.0789
  • 33
    Brown NJ, Rumsey RDE, Bogentoft C, Read NW. The effect of an opiate receptor antagonist on the ileal brake mechanism in the rat. Pharmacology 1993; 47: 2306.
  • 34
    Grider JR, Makhlouf GM. Role of opioid neurons in the regulation of intestinal peristalsis. Am J Physiol 1987; 253: G22631.
  • 35
    Clark SJ, Smith TW. The release of met-enkephalin from the guinea-pig ileum at rest and during peristaltic activity. Life Sci 1983; 33 (Suppl. 1): 4658.
  • 36
    Bartho L, Holzer P, Lembeck F. Is ganglionic transmission through nicotinic receptors essential for the peristaltic reflex in guinea-pig ileum? Neuropharmacology 1987; 26: 16636.DOI: 10.1016/0028-3908(87)90018-9
  • 37
    Tuladhar BR, Naylor RJ. A simple method to study peristalsis in the mouse colon. Gastroenterology 2002; 122 (Suppl. 1): T1077.
  • 38
    Raffa RB, Jacoby HI. Effect of Phe-D-Met-Arg-Phe-NH2 and other Phe-Met-Arg-Phe-NH2-related peptides on mouse colonic propulsive motility: a structure-activity relationship study. J Pharmacol Exp Ther 1990; 254: 80914.
  • 39
    Camilleri M, Malegalada J-R, Stanghellini V, Zinsmeister AR, Kao PC, Li CH. Dose-related effects of synthetic human Beta-endorphin and naloxone on fed gastrointestinal motility. Am J Physiol 1986; 251: 14754.
  • 40
    Welch IMcL, Baxter A, Read NW. Effect of naloxone, domperidone and idazoxan on the delay in gastric emptying caused by ileal lipid. Aliment Pharmacol Ther 1987; 1: 42531.
  • 41
    Kinsman R, Read NW. Effect of naloxone on the feedback regulation of small bowel transit by fat. Gastroenterology 1984; 87: 3357.
  • 42
    Million M, Fioramonti J, Zajac J-M, Bueno L. Effects of neuropeptide FF on intestinal motility and temperature changes induced by endotoxin and platelet activating factor. Eur J Pharmacol 1997; 334: 6773.DOI: 10.1016/S0014-2999(97)01142-4
  • 43
    De Winter BY, Boeckxstaens GE, De Man JG, Moreels TG, Herman AG, Pelckmans PA. Effects of µ- and κ-opioid receptors on postoperative ileus in rats. Eur J Pharmacol 1997; 339: 637.DOI: 10.1016/S0014-2999(97)01345-9
  • 44
    Kreek MJ, Schaffer RA, Hahn EF, Fishman J. Naloxone, a specific opioid antagonist, reverses chronic idiopathic constipation. Lancet 1983; 1: 2612.DOI: 10.1016/S0140-6736(83)91684-7
  • 45
    Kreek MJ, Paris P, Bartol MA, Mueller D. Effects of short term oral administration of the specific opioid antagonist naloxone on fecal evacuation in geriatric patients. Gastroenterology 1984; 86: 1144.
  • 46
    Kaufman PN, Krevsky B, Malmud LS et al. Role of opiate receptors in the regulation of colonic transit. Gastroenterology 1988; 94: 13516.
  • 47
    Yates DA, Santos J, Soderholm JD, Perdue MH. Adaptation of stress-induced mucosal pathophysiology in rat colon involves opioid pathways. Am J Physiol 2001; 281: G1248.
  • 48
    Waterfield AA, Kosterlitz HW. Stereospecific increase by narcotic antagonists of evoked acetylcholine output in guinea-pig ileum. Life Sci 1975; 16: 178792.DOI: 10.1016/0024-3205(75)90275-1
  • 49
    Donnerer J, Holzer P, Lembeck F. Release of dynorphin, somatostatin and substance P from the vascularly perfused small intestine of the guinea-pig during peristalsis. Br J Pharmacol 1984; 83: 91925.
  • 50
    Puig MM, Gasgon P, Musacchio JM. Endorphin release: cross tolerance to morphine. Eur J Pharmacol 1977; 45: 2056.DOI: 10.1016/0014-2999(77)90091-7
  • 51
    Cosentino M, Marino F, Deponti F et al. Tonic modulation of neurotransmitter release in the guinea-pig myenteric plexus: effect of µ and κ opioid receptor blockade and of chronic sympathetic denervation. Neurosci Lett 1995; 194: 1858.
  • 52
    Baur AJ, Szurszewski JH. Effect of opioid peptides on circular muscle of canine duodenum. J Physiol 1991; 434: 40922.