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 μ-opioid 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.

Keywords: beta-arrestin; constipation; opioid; tolerance.

Figure 1

General scheme of the role of β-arrestin2 in the tolerance to morphine in the ileum and colon. Agonist binding to the μ-opioid receptor activates G-protein signaling, and phosphorylation of the receptor by G-protein receptor kinase or protein kinase C dependent on the specific agonist. Phosphorylation leads to recruitment of β-arrestin2. In the ileum, repeated administration of morphine results in down-regulation of β-arrestin2 levels and development of tolerance. In the colon, repeated morphine administration does not affect β-arrestin2 levels and tolerance does not develop. Tolerance in the colon develops in the β-arrestin2 knockout mouse.