Received for publication July 10, 2008.
Revised August 1, 2008.
Accepted for publication August 4, 2008.

Morphine tolerance in the mouse ileum and colon

Abstract

Repeated administration of morphine is associated with tolerance to its antinocicpetive properties. Constipation, however, remains the major side-effect of chronic exposure to morphine. In contrast, previous studies suggest that tolerance to opioids develops in the ileum from several species. In this study, we provide evidence that constipation may arise due to lack of tolerance development to morphine in the colon. Mice were implanted with either placebo or 75 mg morphine pellets and examined for morphine tolerance to antinociception, defecation, intestinal and colonic transit after 72 h. Tissues were obtained from the ileum and distal colon and contractile responses measured from longitudinal and circular muscle preparations. In morphine-pelleted mice, a 5.5 fold tolerance developed to antinociception after 72 h and 53.2 fold in mice receiving an additional daily morphine injection. In both models, intestinal transit but not defecation or colonic transit developed tolerance. In isolated longitudinal muscle, electrical field stimulation- induced cholinergic contractions were dose-dependently inhibited by morphine in both ileum and colon of placebo-pelleted with a pD₂ or 7.1 ±0.4 and 7.8 ±0.4, respectively. However, the dose-response to morphine inhibition was shifted to the right for the ileum from morphine-pelleted mice (pD₂ 5.1 ± 0.4) but not the colon (pD₂ 6.9 ± 0.4). In circular muscle preparations, morphine induced atropine-insensitive contractions in both tissue segments. Tolerance to morphine developed in the ileum but not the colon upon repeated administration of morphine. These findings indicate that lack of tolerance development in the colon is the basis for opioid bowel dysfunction

Key words: Analgesia, Colonic Transit, Constipation, Intestinal Transit, Opioid Bowel Syndrome, Tolerance