Abstract
Repeated administration of morphine results in tolerance to antinociception but not constipation. Tolerance develops to the effects of morphine in the ileum but not the colon. The objective of this study was to identify the intracellular signaling mechanisms responsible for these differences in these two organs. Morphine (100 nM) inhibited field‐stimulation evoked (EFS) cholinergic contractions in longitudinal muscle preparations and produced atropine‐insensitive contractions in the circular muscle from ileum and colon. In the presence of the GRK2 inhibitor, methyl 5‐[2‐(5‐nitro‐2‐furyl)vinyl]‐2‐furoate (100 μM), morphine‐mediated inhibition of EFS contractions in the longitudinal muscle and direct contractions of circular muscle were abolished in the ileum but not the colon. The concentration‐response to acetylcholine in both tissues was not affected by the GRK2 inhibitor. Cell lysates from morphine treated ileum and colon were immunoprecipitated with anti‐GRK2 antibody. Immunoblot with anti‐μ‐receptor (MOR) antibody showed a band of ~70 kDa in the ileum but not the colon demonstrating interaction of MOR with GRK2 in the ileum but not colon and may form the basis for the differential tolerance development between the ileum and colon. Supported by DK46367, DA01647, DA020836
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