Opioid receptors in the gastrointestinal tract

Abstract

Opium is arguably one of the oldest herbal medicines, being used as analgesic, sedative and antidiarrheal drug for thousands of years. These effects mirror the actions of the endogenous opioid system and are mediated by the principal μ-, κ- and δ-opioid receptors. In the gut, met-enkephalin, leu-enkephalin, β-endorphin and dynorphin occur in both neurons and endocrine cells. When released, opioid peptides activate opioid receptors on the enteric circuitry controlling motility and secretion. As a result, inhibition of gastric emptying, increase in sphincter tone, induction of stationary motor patterns and blockade of peristalsis ensue. Together with inhibition of ion and fluid secretion, these effects cause constipation, one of the most frequent and troublesome adverse reactions of opioid analgesic therapy. Although laxatives are most frequently used to ameliorate opioid-induced bowel dysfunction, their efficacy is unsatisfactory. Specific antagonism of peripheral opioid receptors is a more rational approach. This goal is addressed by the use of opioid receptor antagonists with limited absorption such as oral prolonged-release naloxone and opioid receptor antagonists that do not penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Preliminary evidence indicates that peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right.

Introduction

Opium, the dried latex derived from the unripe seed capsules of the opium poppy, Papaver somniferum, is one of the oldest herbal medicines [1]. Its anesthetic and sedating properties are well described in “De Materia Medica” by Pedanius Dioscorides (Pedanios Dioskurides), a Greek physician in the service of the Roman emperor Nero in the 1st century AD [1]. “De Materia Medica” was compilated around 65 AD and is arguably the first textbook of pharmacology ever written. Dioscorides' work has been copied and annotated uncounted times, and the oldest surviving copy is treasured in the Austrian National Library in Vienna and indexed as “Codex Vindobonensis Medicus Graecus 1”. Recognized by UNESCO as a World Heritage book, this so-called “Vienna Dioscorides” dates from about 512 AD and is a superb example of Byzantine book-painting [1].

Apart from its effects to facilitate sleep and remove pain, opium has also been used to treat diarrhea since ancient times. Paracelsus (1493–1541) had such a high opinion of opium that he called it “Laudanum”, and this name was later used to denote alcoholic preparations of opium introduced by Thomas Sydenham (1624–1689) [1]. His famous recipe contained 1 lb of sherry wine, 2 oz of opium, 1 oz of saffron, 1 oz of cinnamon powder and 1 oz of clove powder [2]. Importantly, Sydenham also confirmed the efficacy of Laudanum in the treatment of diarrhea associated with dysentery [2]. The active ingredients of opium (e.g., morphine, noscapine, codeine, thebaine, and papaverine) were isolated in the first half of the 19th century [1]. Although not all of these compounds are ligands of opioid receptors, they are able to affect the function of the gastrointestinal (GI) tract by various mechanisms.

Paul Trendelenburg was arguably the first to discover that morphine inhibits the peristaltic reflex in the gut [3], a finding that he reported in his classic text on “Physiologische und pharmakologische Versuche über die Dünndarmperistaltik”, now available in an English translation [4]. Ever since, investigators were intrigued by the physiologic meaning of this discovery, and Otto Schaumann interpreted the pharmacologic effects of exogenous opiates on pain and bowel function as indicative of an endogenous protective system [5]. Schaumann [5] and William D.M. Paton [6] showed that morphine inhibited the release of acetylcholine in the isolated guinea pig ileum, and electrophysiologic studies began to reveal that opiates inhibit the function of the enteric nervous system [7].

After the identification of opiate receptors by Solomon H. Snyder and other investigators [8] the search was out for their endogenous ligand. In 1975, Hans Kosterlitz, together with John Hughes, identified leucine-enkephalin and methionine-enkephalin as the first endogenous opioid receptor agonists [9]. These pentapeptides were also found to occur in the gut [10], and subsequent analysis of their functional implications revealed that opioid receptor agonists interact with pathways of the enteric nervous system that regulate GI motility and secretion [11], [12], [13], [14], [15]. In addition, there is evidence that some GI effects of opioid receptor agonists may be mediated by opioid receptors in the brain [16]. However, experimental and clinical studies with opioid receptor antagonists that are unable to enter the brain have shown that the GI effects of opioid analgesics arise from a peripheral site of action [16].

The current review starts by providing a brief overview of the neurobiologic mechanisms whereby opioids modify GI function. After addressing the use of opioid receptor agonists as antidiarrheal drugs, the article goes on to discuss emerging strategies to avoid opioid-induced bowel dysfunction (OBD) and the clinical utility of peripheral opioid receptor antagonists.