Site and mechanism of morphine tolerance in the gastrointestinal tract

Abstract

Opioid-induced constipation is a major clinical problem. The effects of morphine, and other narcotics, on the gastrointestinal tract persist over long-term use thus limiting the clinical benefit of these excellent pain relievers. The effects of opioids in the gut, including morphine, are largely mediated by the μ-opioid receptors at the soma and nerve terminals of enteric neurons. Recent studies demonstrate that regional differences exist in both acute and chronic morphine along the gastrointestinal tract. While tolerance develops to the analgesic effects and upper gastrointestinal motility upon repeated morphine administration, tolerance does not develop in the colon with chronic opioids resulting in persistent constipation. Here, we review the mechanisms by which tolerance develops in the small but not the large intestine. The regional differences lie in the signaling and regulation of the μopioid receptor in the various segments of the gastrointestinal tract. The differential role of β-arrestin2 in tolerance development between central and enteric neurons defines the potential for therapeutic approaches in developing ligands with analgesic properties and minimal constipating effects.

The Impact of Opioid Treatment on Regional Gastrointestinal Transit

“…[34][35][36] Recent in vitro studies in rodents has demonstrated tolerance to opioids in the upper, but not the lower GI tract. 37,38 Therefore differences in tolerance may partly explain our findings although direct translation to human in vivo physiology is highly questionable. 39 No associations between questionnaire scores and transit times were found.…”

Colorectal Transit and Volume During Treatment With Prolonged-release Oxycodone/Naloxone Versus Oxycodone Plus Macrogol 3350

“…However, previous animal studies suggest that while tolerance may develop to the analgesic effects and upper GI motility upon repeated morphine administration, tolerance does not develop in the colon. 35,36 To the authors knowledge no similar studies exist in humans, but if the preclinical results can be translated to humans, the outcomes of a clinical study would likely be either similar to ours or potentially more profound due to the longer treatment and/or higher doses. Nonetheless, in clinical studies, confounding factors that can affect gut function, such as concomitant drug use, immobility, dehydration, anxiety, depression, and anorexia are difficult to avoid and may bias results.…”

Peripherally acting μ-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy

“…OIC can limit opioid therapy and may adversely impact patient adherence, adequate pain control, and patient function and in rare case even causes stercoral perforation, a potentially fatal complication 9,10. Treatment options for OIC have typically included a bowel regimen with lifestyle modifications and nonpharmacological strategies to be supplemented with conventional laxatives.…”