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Morphine tolerance and dependence in the rat intestine in vivo
C L Williams1, C C Bihm, G C Rosenfeld
1Department of Pharmacology, The University of Texas Houston Health Science Center, 77225, USA.
Abstract:
There has been no previous demonstration of opioid tolerance and dependence with respect to the propulsive and contractile activities of the gut in vivo. In the experiments described herein, morphine was administered continuously (1 mg/kg/hr s.c., 72 hr) and/or by bolus injection (2 mg/kg) and intestinal motility and transit were evaluated in unanesthetized rats. Tolerance in intestinal motility (contractions) and propulsion (transit) was measured in two ways, i.e., by measuring the time required for motility and propulsion to return to control values and by measuring the loss of effectiveness of bolus morphine administered to animals receiving continuous infusion of the opiate. The dose of morphine chosen for continuous administration (1 mg/kg/hr s.c. via Alzet minipumps) was based on the dose at which morphine inhibited intestinal propulsion by 50%. Morphine (1 mg/kg/hr) decreased the frequency of contractions in, and propulsion along, the small bowel and colon and produced mild antinociception. The frequency of duodenal and colonic contractions returned to normal within 13 to 16 hr. After 24 hr of morphine treatment, the inhibitory effects of bolus doses of morphine on motility and transit were diminished; the effects were eventually lost (48 hr). Similarly, the antinociceptive effects of bolus doses of morphine were diminished by 18 hr and lost by 24 hr. Naloxone (0.1 mg/kg s.c.) given to morphine-tolerant animals (72 hr) resulted in an increase in the frequency and amplitude of contractions in the colon, an increase in the propulsive activity of the small intestine and colon and diarrhea. These results provide direct demonstration of opioid tolerance and dependence of contractile and propulsive activity in the rat intestine in vivo.
Insights
This study demonstrates opioid tolerance and dependence in rat gut motility. Continuous morphine administration led to reduced intestinal contractions and transit, with effects reversing upon naloxone administration.
Area of Science:
- Gastroenterology
- Pharmacology
- Neuroscience
Background:
- Opioid medications significantly impact gastrointestinal (GI) function.
- Previous research has not conclusively demonstrated opioid tolerance and dependence in gut motility in vivo.
Purpose of the Study:
- To investigate and demonstrate opioid tolerance and dependence in the propulsive and contractile activities of the rat gut.
- To evaluate the effects of continuous and bolus morphine administration on intestinal motility and transit.
Main Methods:
- Unanesthetized rats received continuous subcutaneous morphine infusion (1 mg/kg/hr for 72 hr) and/or bolus injections (2 mg/kg).
- Intestinal motility (contractions) and propulsion (transit) were measured.
- Tolerance was assessed by the return of motility to baseline and the diminished effectiveness of bolus morphine doses.
- Antinociceptive effects were also monitored.
Main Results:
- Continuous morphine administration reduced the frequency of contractions and propulsion in the small bowel and colon.
- Tolerance to morphine's effects on motility and transit developed within 24-48 hours.
- Antinociceptive effects also diminished, with tolerance developing by 18-24 hours.
- Naloxone administration to tolerant rats reversed these effects, inducing increased contractions, propulsion, and diarrhea.
Conclusions:
- This study provides the first direct demonstration of opioid tolerance and dependence in the contractile and propulsive activities of the rat intestine in vivo.
- These findings have implications for understanding and managing opioid-induced gastrointestinal side effects.