Opioids and the Gastrointestinal Tract: The Role of Peripherally Active µ-Opioid Receptor Antagonists in Modulating Intestinal Permeability

Abstract

Opioid receptors are found throughout the gastrointestinal tract, including the large intestine. Many patients treated with opioids experience opioid-induced constipation (OIC). Laxatives are not effective in most patients, and in those who do initially respond, the efficacy of laxatives generally diminishes over time. In addition, OIC does not spontaneously resolve for most patients. However, complications of opioids extend far beyond simply slowing gastrointestinal transit. Opioid use can affect intestinal permeability through a variety of mechanisms. Toll-like receptors are a crucial component of innate immunity and are tightly regulated within the gut epithelium. Pathologic µ-opioid receptor (MOR) and toll-like receptor signaling, resulting from chronic opioid exposure, disrupts intestinal permeability leading to potentially harmful bacterial translocation, elevated levels of bacterial toxins, immune activation, and increased cytokine production. Peripherally active MOR antagonists, including methylnaltrexone, are effective at treating OIC. Benefits extend beyond simply blocking the MOR; these agents also act to ameliorate opioid-induced disrupted intestinal permeability. In this review, we briefly describe the physiology of the gastrointestinal epithelial border and discuss the impact of opioids on gastrointestinal function. Finally, we consider the use of peripherally active MOR antagonists to treat disrupted intestinal permeability resulting from opioid use and discuss the potential for improved morbidity and mortality in patients treated with methylnaltrexone for opioid-induced bowel disorders.

Figure 1.

Layers of the gastrointestinal lumen (15,16). Transport in and out of the gastrointestinal lumen is regulated by the mucosa, which consists of a monolayer of epithelial cells and a secreted mucinous layer overlying the epithelial cell layer (15,16). The submucosal layer lies beneath the epithelial cell layer and consists of a loose matrix of extracellular material (e.g., glycosaminoglycans) (17) with embedded neurons and other supporting cells, such as glia (11). Movement of solutes out of the lumen occurs through transcellular and paracellular transport (20). Paracellular transport through the epithelial monolayer is limited by a network of TJs (16). Protein components of TJs include the claudins, occludin, tricellulin, and junctional adhesion molecules. TJ, tight junction.

Figure 2.

Regulation of intestinal secretion and peristalsis through µ-opioid receptors (26,27). µ-opioid receptor signaling regulates intestinal secretion and peristalsis by binding to the endogenous opioids met-enkephalin, dynorphin, beta-endorphin, and endomorphins, which are released by several cell types, including enteric neurons, endocrine cells, and immune cells (26,27).

Figure 3.

Effect of morphine treatment on TJs (9,16). Morphine increases intestinal permeability by altering the function and organization of TJs between gut epithelial cells of the small intestine. Morphine disturbs the TJ organization and function by disrupting the localized expression of the occludin and zona occludens 1 proteins (9). TJ, tight junction.

Figure 4.

Effects of morphine signaling on the intestinal barrier (,,–,–31,66,67). Activation of MORs in the gastrointestinal tract can lead to bowel dysfunction and symptoms of constipation (26,27). MOR, µ-opioid receptors.

Figure 5.

Morphine leads to microbial dysbiosis, disrupting gut homeostasis, and bacteria translocation (44). Exposure to morphine or other opioids substantially alters the microbiota of the intestine. Studies of human flora have revealed increased numbers of Bifidobacterium with decreased colonization by Bacteroidacea, Clostridiales XIV, and Ruminococcaceae (43). Morphine-induced increases in intestinal permeability may be reduced through the administration of antibiotics (45).

Figure 6.

Chemical structures of FDA-approved medications for OIC. FDA, Food and Drug Administration; OIC, opioid-induced constipation.