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The ‘state of the art’ of current understanding of the role of opioid receptors in the gastrointestinal (GI) tract is contained in the preceding papers in this supplement. Our aim was to build the foundation for a greater understanding of opioids and their receptors in the GI tract and how opiate analgesics produce marked stasis of the bowel, and thus self-limit their utility in clinical practice. Given the effects of opiates on peripheral (somatic) sensation, a second goal was to consider the potential for modulation of sensations emanating from the bowel. As with most collections of reviews of this type, the focus has been upon what is currently known from published literature of studies in animals or animal tissue. Novel data presented here, however, add further to our understanding of this important system. We have compiled a package of information encompassing molecular and anatomical studies to in vivo physiology and behaviour, with the goal of understanding the effects of exogenous and endogenous opioids on GI function in humans.

Much work has been directed toward investigating the role of opioids in the enteric nervous system (ENS), the key neuronal control centre for GI motility and secretion. The ENS was also the site at which some of the initial characterizations of opioid receptor pharmacology and physiology were conducted.1–4 However, the collection of papers here also reviews the role of opioid receptors on extrinsic afferent nerves conveying information to the brain, interstitial cells of Cajal, endocrine and inflammatory cells, and other sites. These elements have been implicated in the overall effects of opioids in GI function.

The aim of these final few pages is not to repeat and summarize the content of the preceding chapters, but rather to highlight areas where further work is needed in order for the opioid systems in the GI tract to be better understood.

The major problem that has been highlighted in this supplement is the paucity of knowledge of the role of opioids in the ENS in humans. Clearly, the GI outcomes related to µ opiate analgesic use are well known,5,6 but as with most other systems, our mechanistic understanding of how these effects are mediated comes primarily from studies in animals. For understanding the opioid system, such extrapolation presents a major problem, as species differences in receptor and ligand distribution,7 and in function at the whole tissue level,8 are considerable. For this reason, expert laboratories are working to define precisely the distribution and function of opioid receptors in the human GI tract, and the hope is that, in the future, these studies will be extended to include investigation of potential changes in diseased tissues. Of course, the elegant data from Dr Sternini's laboratory demonstrating laparotomy-induced µ-receptor internalization into myenteric neurones will need to be considered in the design of this work, in which tissue from surgical resections is commonly used. Indeed, as suggested by Sternini et al.,7 the potential for a role of such receptor endocytosis in the production of opiate analgesic side effects, or in the ileus response to abdominal surgery would be an extremely interesting avenue for further exploration. One of the most exciting findings emanating from these studies is that suggesting endogenous opioid release during surgery and bowel manipulation is responsible for the internalization of µ-receptors, and that this is prevented by selective µ-receptor antagonists. If there is a role for this antagonist-sensitive phenomenon in postoperative ileus (POI), or in pathophysiological states associated with constipation in humans, there appears to be a significant potential for µ-receptor antagonist therapy and further study is warranted.

Although we cannot at this time describe the definitive distribution of opioid receptors in the human GI tract, it is clear that components of the ENS, particularly Dogiel Type I motor and interneurones, are likely to be key in mediating the effects of opioids. The studies described by Wood and Galligan9 showed how opioids function to inhibit neurotransmitter release by both pre- and postsynaptic actions. For example, a range of classical inhibitory G-protein coupled receptor activity results from µ-receptor activation. Thus, K+ channels are activated, Ca+ channels closed, and production of cAMP inhibited. Other ion channels such as Kv1.1 may also be activated.10 Since inhibition of both excitatory and inhibitory neurones has been demonstrated by opioid receptor activation, it is likely that endogenous opioids play a neuromodulatory role in ENS function, rather than acting as primary neurotransmitters. The overall effect of opiates and opioids is to act as a brake on ENS activity. In this role, the timing of release of endogenous opiates is critical, in order to maintain the correct sequence of electrophysiological events in the ENS for co-ordinated propulsive motility. This delicately balanced pattern generator is very sensitive to change, especially in the form of a flood of endogenous opioids resulting from inflammatory processes11 or in response to opiate analgesic agents. Under these circumstances the coordinated patterns break down, and disordered, non-propulsive contractile activity results. When coupled with additional activities upon secretion, and upon central nervous systems (CNS) (both spinal cord and brain) involved in the control of bowel function,9 the overall result is inhibition of GI propulsive activity that may present as nausea, vomiting or severe constipation.

Indeed, this is a conclusion drawn from the data reviewed by Sanger and Tuladhar,8 in which it was suggested that endogenous opioids have a negligible effect upon normal intestinal physiology, but function to suppress intestinal motility when motor function is by some means compromised. Under these pharmacologically or pathophysiologically induced conditions, the prokinetic activity of opioid receptor antagonist drugs may be revealed. This view is supported further by in vivo data cited in the papers by Grundy et al.12and Greenwood-Van Meerveld et al.13 showing no effects of peripherally acting µ-opioid antagonists upon either sensory or motor functions, although the effects of agonists in both studies were potently reversed. Thus, peripherally acting µ-opioid antagonists did not alter afferent nerve activity, or sensitivity to chemical or mechanical stimuli in rats, or normal GI transit in either rats or mice; on the other hand, effects of agonists in both studies were potently reversed. Further work is required to elucidate the opioid receptor subtype(s) involved in the control of GI transit. The data reviewed by Sanger and Tuladhar8 illustrates clearly the complexity and difficulties in studying the motor function of the GI tract in vitro. Such studies are, however, very informative, and critical to our understanding of the pharmacology of GI function. The elegant methods described, currently in development for assessment of peristalsis in multiple species, will provide the ability to investigate these questions in a way that is more predictive of outcomes observed in the in vivo laboratory and clinic.

Another question that needs further study is: ‘Are opioid receptors the final point in the chain of events leading to inhibition of GI transit by multiple transmitters?’. Data from in vitro studies in guinea-pig colon8 show that the inhibitory actions of 5-HT3 receptor antagonists and α2-adrenoceptor agonists are blocked by naloxone. However, similar results were not observed in vivo in rats, where alvimopan did not prevent the inhibitory action of para-amino clonidine (a clonidine derivative with minimal CNS penetration). These findings appear contradictory at first glance; however, there are clearly many differences between these studies, including species, antagonist selectivity, antagonist disposition profile and, not least, the in vitro vs. in vivo design. The question as to whether opiate antagonists effectively block the inhibition of gut functions by concomitantly administered 5-HT3 receptor antagonists and α2-adrenoceptor agonists is therefore still open, and this has implications for the potential use of opiate-related medicines for GI disorders where the aetiology is complex or unknown.

Another intriguing possible role for opioids that requires further investigation is the potential for the concomitant administration of µ-opioid receptor antagonists with 5-HT4 receptor agonists, given the observation by Foxx-Orenstein et al.14 that there is synergism in the induction of propulsive transport in a classical peristalsis model. Whether this is limited to an in vitro technique or represents another potential role of the opioid receptors in modulating gut motor function is the topic of ongoing research in humans.

Our understanding of the precise mechanisms involved in opioid-induced slowing of GI transit is far from complete; the role of extrinsic nerves, and of the CNS is even less clear and needs greater attention in the future. A CNS component of both motility and secretory effects of opioids, involving stimulation of sympathetic outflow to the ENS, is discussed in detail by Wood and Galligan.9 Grundy et al.12 describe a direct effect of opiates, acting at the µ-receptor, upon afferent nerves, the communication pipeline between the gut and the brain. Both vagal and spinal afferent systems have been extensively studied with respect to their role in sensory signalling of noxious sensations (visceral pain, nausea), and clinical effects of κ-receptor agonists have been described.5 Less attention has been devoted to the role of µ-opioid receptors in the extrinsic afferent nerves, from both the sensory and motility perspectives. For this reason, Grundy et al.12 have studied the sensitivity of mesenteric afferents supplying the rat small intestine to µ-opioid receptor ligands, and used the peripherally acting µ-receptor antagonist alvimopan to examine the role of endogenous opioids in regulating mesenteric afferent sensitivity. Considering the classically described inhibitory effect of opiates upon neuronal activity, the marked stimulation of vagal afferent nerves innervating the rat small intestine produced by the selective µ-opioid receptor agonist DAMGO is unusual and fascinating. The potential for this vagal nerve activation to play a role in opiate-induced disturbed GI transit (via stimulation of cholecystokinin-sensitive fibres, leading to a gastric relaxation) and nausea and vomiting is a conclusion that is consistent with a large body of prior literature. The role of the vagal nerve in modulation of nociception is less well characterized, but this does not reduce the importance of these data and their implications relative to the potential perioperative use of peripherally acting µ-receptor antagonists. As suggested by Grundy et al.12 it is unlikely that blockade of this peripheral input would lead to a loss of overall analgesia produced by CNS actions of opiates, but the only true test of this will, of course, be in formal clinical trials.

Studies in vivo have defined roles for opioid receptors in GI transit, the clearest evidence existing for the inhibitory effect of µ-receptor activation by agonists such as morphine. The role of opioids in sensory signalling from the bowel is less clear, especially with respect to the well-documented role of κ receptors in the inhibition of noxious signals from the colon. As described by Grundy et al.12 and Greenwood-Van Meerveld et al.,13 sodium channel-blocking activity of the drugs used to define the analgesic effects as being mediated through κ receptors has brought this conclusion into question. The novel data presented in the same chapter, concerning the potential existence of an ongoing ‘inhibitory tone’ in the colorectal sensory system, is worthy of further study in order to define more precisely its locus and the nature of this endogenous opioid activity. The ‘proalgesic’ action of naloxone in this rat model, but the absence of similar effects of alvimopan, suggests that the inhibitory tone is either mediated via an action at opioid receptors in the CNS, or at receptors other than µ-opioid receptors. While these experiments confirm that there is no proalgesic potential of peripherally acting µ-opioid receptor drugs, the finding that an ‘opioidergic tone’ might exist in GI sensory system highlights another avenue for study.

With respect to the potential roles of opioids in GI disorders, we focused much of our attention in this discussion around POI. This is the situation where slowing of GI transit associated with certain types of surgery is aggravated by concomitant administration of opiate analgesics. This provides an important context of a ‘role for opioid receptors’. Other clinically relevant situations with a role of endogenous opioids in other GI diseases are opioid bowel dysfunction, and possibly chronic constipation and irritable bowel syndrome. In the paper by Bauer and Boeckxstaens,11 we learn about the wide range of mechanisms thought to underlie the inhibition of GI transit observed in POI, and appreciated that no single event is likely to be responsible. Inhibitory neuronal reflexes, release of inflammatory mediators and elements of the physiological response to stress, both at a CNS and local tissue level, act in concert to produce the overall effect of slowing of GI transit. However, what remains unclear at this time is the contribution of endogenous opioid peptides in the POI response. Studies to investigate this are ongoing.

Our understanding of the role of opiates in human GI function (motility, secretion and inflammation) is currently somewhat limited. Further work to help with our knowledge of the basic mechanisms underlying opiate effects, such as receptor distribution and pharmacology, will increase our understanding of the role of opiates and endogenous opioid peptides in normal and pathophysiological states.

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