Opioid receptors Gastrointestinal tract

The 5-HT3 receptor is the only monoamine neurotransmitter receptor that functions as a lig-and-gated ion channel, controlling the flux of Na-i- and K+ ions. 5-HT3 receptors are located on parasympathetic nerve terminals in the gastrointestinal tract, and high densities are found in areas of the brain associated with the emetic response, such as the area postrema. The antiemetic effects of 5-HT3 antagonists, such as ondansetron, result from actions at these sites. 5-HT3 receptors in the dorsal horn of the spinal cord have been implicated in nociception and development of new 5-HT3 receptor-related compounds may have potential as non-opioid, non-addictive analgesics. 

The gastrointestinal tract is the only system outside the central nervous system (CNS) with significant concentrations of opioid receptors. This reflects their common embryonic origins. Opioids increase intestinal tone and decrease propulsive peristalsis, resulting in delayed gastric emptying and constipation or ileus. Opioids increase common bile duct pressure and decrease bile production and flow, primarily because of spasm of the sphincter of Oddi. The tone of the bile duct itself is also increased. 

Opioids act by attaching to specific proteins called opioid receptors, which are found in the brain, spinal cord, and gastrointestinal tract. When these compounds attach to certain opioid receptors in the brain and spinal cord, they can effectively change the way a person experiences pain. 

We started out our studies on amphibian opioid peptides in the wake of the explosion of research on mammalian endogenous ligands for opiate receptors. We asked ourselves whether the never disappointing amphibian skin contained related molecules. The question was reasonably posed in the light of the outcome of our previous, yearlong research showing that amphibian skin peptides often had counterparts in mammalian CNS and gastrointestinal tract [1]. 

Recent investigations have revealed that the delta opioid receptor also is involved in the modulation of gastrointestinal functions, particularly in mammals other than the guinea pig. In this chapter, we will discuss the presence and roles of this opioid receptor type in mediating the actions of opioid drugs and their endogenous counterparts in the digestive tract. 

Subsequent to the molecular cloning and cDNA sequence analysis of the delta opioid receptor, antireceptor antibodies were raised against synthetic peptides based on the deduced amino acid sequence of this receptor. To date, there have been a limited number of studies using antibodies directed toward the amino terminus of the cloned murine receptor to assess the distribution of delta opioid receptorlike immunoreactivity in the gastrointestinal tract, and these have been confined so far to the porcine small intestine. They have shown the presence of delta opioid receptor-immuno-reactive neurons and fibers in both the myenteric and submucosal plexuses and as well as in myenteric neurons maintained in primary culture [22, 23]. Receptor-like immunoreactivity in neuronal cell bodies appears to be localized in the cytoplasm and is likely to be trafficked to nerve terminals. These neurons are coimmunoreactive for the acetylcholine-synthesizing... 

PERSPECTIVES ON THE ROLE OF DELTA OPIOID RECEPTORS IN THE GASTROINTESTINAL TRACT... 

Mechanism of action Opioids exert their major effects by interacting with opioid receptors in the CNS and the gastrointestinal tract. Opioids cause hyperpolarization of nerve cells, inhibition of nerve firing, and presynaptic inhibition of transmitter release. Morphine acts at k receptors in lamina I and II of the substantia gelatinosa of the spinal cord, and decreases the release of substance P, which modulates pain perception in the spinal cord. Morphine also appears to inhibit the release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli. 

Tramadol is an opioid with additional actions the basis of its analgesic effects appears to derive from a combination of (relatively weak) agonist action on p-receptors, inhibition of neuronal noradrenaline uptake and enhanced serotonin release. It is rapidly absorbed from the gastrointestinal tract, 20% of an oral dose undergoes first-pass metabolism and less than 30% dose is excreted unchanged in the urine (W2 6 h). Tramadol is approximately as effective as pethidine for postoperative pain and as morphine for moderate chronic pain. 

Fedotozine (Jo-1196,170), which is structurally related to the acyclic k agonists, has in vivo antinociceptive effects on duodenal pain that appear to be mediated by peripheral k opioid receptors, but the compound is inactive after central administration (544). In binding assays (in dog myenteric plexus), however, this compound exhibits similar affinity = 0.3-0.8 jM) for all three types of opioid receptors (545). Unlike other k agonists, fedotozine does not induce diuresis after either s.c. or in-tracerebroventricular (i.c.v.) administration (546). Fedotozine also fails to substitute for either U50,488 or morphine in animals trained to discriminate these drugs (547). The main effects demonstrated for fedotozine have been in the gastrointestinal tract (seeRef 548 for a detailed review of the pharmacology of fedotozine), and therefore this compound has... 

Holzer P (2009) Opioid receptors in the gastrointestinal tract. Regul Pept 155 11-17... 

The predominant action of cannabinoid receptor agonists on the GI tract is an inhibitory effect on gastrointestinal motility, reminiscent of the neuromodulatory response to presynaptic p-opioid receptor or 02 -adrenoceptor activation of cholinergic, postganglionic parasympathetic neurons. The mechanisms underlying this effect have been studied chiefly in the GI tract of small rodents, but also in man and the pig. Here we shall review the findings of studies carried out in vitro (Sect. 3.1, below) and in vivo (Sect. 3.2). 

Gastrointestinal constipation and nausea are common. Nausea may be treated with antiemetics, and frequently improves with ongoing therapy. Virtually all patients taking opioids become constipated and do not become tolerant to this side effect. Activation of mu receptors in the gastrointestinal tract slows peristalsis, which promotes further absorption of water and electrolytes in the colon. Patients should be treated prophylactically with stool softeners and/ or laxatives. There is an oral oxycodone/naloxone prolonged-release tablet in clinical trials to counteract opioid-induced constipation, which is often debilitating. 

It is absorbed both neuraxially and systemically. DepoDur has a principal effect on opioid receptors in the dorsal horn of the spinal cord as well as in other regions of the central nervous system (CNS). Additionally, it works in the gastrointestinal (GI) tract and other smooth muscles. However, it does not have a major effect on the cardiovascular system at therapeutic doses. 

Receptor interactions the primary effects of methyinaltrexone are mediated by antagonism of mu opioid receptors in the gastrointestinal tract. These receptors are primarily concentrated in neural cells and termi-... 

Opioids are analgesics that work by binding to the opioid receptors found on neurons in various areas of the brain and spinal cord as well as intramural plexuses that regulate the motility of the gastrointestinal and urogenital tracts. Opiates are by definition limited to natural opium alkaloids and their semi-synthetic derivatives. Morphine,... 

---