Repeated administration of
morphine is associated with tolerance to its antinociceptive properties. However,
constipation remains the major side effect of chronic exposure to
morphine. In contrast, previous studies suggest that tolerance to
opioids develops in the ileum of several species. In this study, we provide evidence that
constipation may arise due to a lack of tolerance development to
morphine in the colon. Mice received implants with either placebo or 75 mg of
morphine pellets, and they were examined for
morphine tolerance to antinociception, defecation, and intestinal and colonic transit after 72 h. Tissues were obtained from the ileum and distal colon, and contractile responses were measured from longitudinal and circular muscle preparations. In
morphine-pelleted mice, a 5.5-fold tolerance developed to antinociception after 72 h, and a 53.2-fold tolerance developed in mice that received an additional daily
morphine injection. In both models, intestinal transit but not defecation or colonic transit developed tolerance. In isolated longitudinal muscles, electrical field stimulation-induced
cholinergic contractions were dose-dependently inhibited by
morphine in both the ileum and colon of placebo pelleted with a pD(2) of 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 (pD(2) = 5.1 +/- 0.4) but not the colon (pD(2) = 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 a lack of tolerance development in the colon is the basis for
opioid bowel dysfunction.