Morphine‐induced tolerance and dependence develops in the mouse isolated ileum but not colon

Abstract

Morphine tolerance and dependence have been demonstrated historically in ileum but not in the colon, the major organ associated with constipation. Here we evaluated the development of tolerance and dependence to morphine in the isolated tissue segments from the mouse ileum and colon. Isometric force was measured from longitudinal and circular muscle preparations of ileum and colon from placebo‐ (PP) and morphine‐pelleted (MP) mice. Morphine inhibition of field stimulated contractions of the longitudinal muscle was dose dependent with comparable pD2 values from the ileum (7.1) and colon (7.8) (n=6) of PP mice. However, the dose‐response was shifted to the right for the ileum (pD2= 5.1) but not the colon (pD2= 6.9) of MP mice. Morphine produced contractions of circular muscle preparations in ileum and colon. Repeated administration of morphine in the organ bath produced tolerance in the ileum by the 4th application but not the colon from PP mice. Whereas in tissues from MP mice, where tolerance has already developed, further tolerance to the contractile response to morphine did not develop in the ileum. Naloxone precipitated a withdrawal contracture in the longitudinal muscle after long‐term morphine incubation in the ileum but not the colon. These findings demonstrate that tolerance does not develop in the colon and may explain the lack of tolerance to morphine‐induced constipation. Supported by DK46367, DA01647