Faculty Collaboration Database

Morphine tolerance in the mouse ileum and colon. J Pharmacol Exp Ther 2008 Nov;327(2):561-72

Date

08/07/2008

Pubmed ID

18682567

Pubmed Central ID

PMC2574683

DOI

10.1124/jpet.108.143438

Scopus ID

2-s2.0-54349120029 (requires institutional sign-in at Scopus site)   69 Citations

Abstract

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.

Author List

Ross GR, Gabra BH, Dewey WL, Akbarali HI

Author

Gracious R. Ross Research Scientist II in the Cardiovascular Center department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetylcholine
Analgesics, Opioid
Animals
Colon
Defecation
Dose-Response Relationship, Drug
Drug Tolerance
Gastrointestinal Transit
Ileum
Male
Mice
Morphine
Muscle Contraction
Muscle, Smooth