Abstract
β-arrestin2 has been reported to play an essential role in analgesic tolerance. Analgesic tolerance without concomitant tolerance to constipation are limiting side-effects of chronic morphine treatment. Since tolerance to morphine develops in the mouse ileum but not the colon, we therefore examined whether the role of β -arrestin2 in the mechanism of morphine tolerance differs in the ileum and colon. In both guinea pig and mouse, chronic in-vitro exposure (2 hours, 10 μM) to morphine resulted in tolerance development in the isolated ileum but not the colon. The pIC50 for morphine-induced inhibition of electrical field-stimulated (EFS) contraction of guinea pig longitudinal muscle myenteric plexus (LMMP) rightward shifted in the ileum from 5.7 ± 0.08 (n=9) to 5.45 ± 0.09 (n=6) (p<0.001) following morphine exposure. A significant shift was not observed in the colon. Similar differential tolerance was seen between the mouse ileum and colon. Tolerance, however, developed in the colon from β-arrestin2 knock-out mice. β -arrestin2 and ERK 1/2 expression levels were further determined by Western blots in guinea pig LMMP. A time-dependent decrease in expression of β -arrestin2 and ERK 1/2 occurred in the ileum but not the colon following 2 hour morphine (10 μM) exposure. Naloxone prevented the decrease in β-arrestin2. In the isolated ileum from guinea pigs chronically treated in-vivo with morphine for 7 days, neither additional tolerance to in-vitro exposure of morphine nor decrease in β-arrestin2 occured . We conclude that a decrease in β -arrestin2 is associated with tolerance development to morphine in the gastrointestinal tract
- Received July 22, 2011.
- Revision received November 23, 2011.
- Accepted November 28, 2011.
- The American Society for Pharmacology and Experimental Therapeutics