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Differential tolerance to the intestinal inhibitory effect of opiates in mice
Abstract:
The occurrence of unidirectional noncross-tolerance to heroin and etorphine induced antinociception in morphine tolerant mice prompted this study to determine whether this phenomenon occurs for opiate induced inhibition of intestinal transit. Tolerance to the intestinal inhibitory effect (charcoal meal test) of s.c. morphine, etorphine and heroin was reflected by an increase in the ED50 value and in most cases, a flattening of the dose response curve in morphine and etorphine pelleted mice (tested with pellet in place). A similar response was noted following intracerebroventricular administration of these agents in morphine pelleted mice. More tolerance developed to the relatively hydrophilic compound morphine than to the lipophilic compounds etorphine and heroin. Factors related to hydrophilicity and lipophilicity may be involved in the development of tolerance to opiates in the intestine although unidirectional non cross-tolerance did not occur.
Insights
This study investigated opioid tolerance in mice, finding that while tolerance to morphine, heroin, and etorphine
Area of Science:
- Pharmacology
- Gastroenterology
- Neuroscience
Background:
- Opioid medications are widely used for pain management.
- Tolerance to opioids can limit their long-term efficacy.
- Understanding opioid tolerance mechanisms is crucial for developing safer analgesics.
Purpose of the Study:
- To investigate the development of tolerance to the intestinal inhibitory effects of morphine, heroin, and etorphine in mice.
- To determine if unidirectional non-cross-tolerance occurs for opioid-induced inhibition of intestinal transit.
Main Methods:
- Mice were made tolerant to opioids by subcutaneous pellet implantation.
- Tolerance was assessed using the charcoal meal test to measure intestinal transit.
- Dose-response curves and ED50 values were analyzed.
- Intracerebroventricular administration was also used to assess central effects.
Main Results:
- Tolerance to the intestinal inhibitory effects of morphine, etorphine, and heroin was observed.
- Increased ED50 values and flattened dose-response curves indicated tolerance.
- More tolerance developed to morphine (hydrophilic) than to etorphine and heroin (lipophilic).
- Unidirectional non-cross-tolerance was not observed in this model.
Conclusions:
- Opioid tolerance affects intestinal transit, with varying degrees based on compound lipophilicity.
- Hydrophilicity and lipophilicity play a role in the development of opioid tolerance in the gastrointestinal tract.
- The phenomenon of unidirectional non-cross-tolerance was not demonstrated for intestinal effects.