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Effects of 5-HT receptor antagonists on morphine-induced tolerance in mice
M R Zarrindast1, M Sajedian, M Rezayat
1Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Iran.
Abstract:
The effect of 5-HT receptor antagonists on tolerance to morphine antinociception was studied in mice. Slow release morphine suspension was injected subcutaneously (s.c.) in order to produce tolerance. When different doses of morphine (3, 6 and 9 mg/kg) were administered on the 4th day after injection of slow-release morphine suspension, tolerance to the test doses of morphine was observed. The tolerance obtained was decreased by pretreatment with the non-selective 5-HT receptor antagonist methysergide (1 and 2 mg/kg) or the 5-HT2 receptor antagonist ritanserin (1 and 2 mg/kg). When the 5-HT receptor antagonists were used on the 2nd and 3rd day after injection of slow-release morphine suspension or on the 4th day (60 min before last dose of morphine), a maximum reduction in morphine tolerance was observed on the 3rd day. Pretreatment of animals with metergoline (1 and 2 mg/kg) or mianserin (1 and 2 mg/kg) also decreased the tolerance to morphine. It may be concluded that at least a 5-HT2 receptor mechanism is involved in tolerance to morphine antinociception.
Insights
Serotonin (5-HT) receptor antagonists, like ritanserin, reduce morphine tolerance in mice. This suggests a 5-HT2 receptor mechanism is involved in the development of morphine antinociception tolerance.
Area of Science:
- Pharmacology
- Neuroscience
- Pain Management
Background:
- Opioid analgesics, such as morphine, are widely used for pain relief.
- Development of tolerance to morphine's antinociceptive effects limits its long-term efficacy.
- The role of serotonin (5-HT) receptors in modulating opioid tolerance is not fully understood.
Purpose of the Study:
- To investigate the effect of 5-HT receptor antagonists on the development of tolerance to morphine antinociception in a mouse model.
- To determine if specific 5-HT receptor subtypes are involved in morphine tolerance.
Main Methods:
- Tolerance to morphine antinociception was induced in mice using a slow-release morphine suspension.
- Various doses of morphine were administered on day 4 to assess tolerance.
- Mice were pretreated with non-selective and selective 5-HT receptor antagonists (methysergide, ritanserin, metergoline, mianserin) at different time points.
Main Results:
- Pretreatment with non-selective 5-HT receptor antagonist methysergide and 5-HT2 receptor antagonist ritanserin significantly decreased morphine tolerance.
- Maximum reduction in morphine tolerance was observed when 5-HT receptor antagonists were administered on the 3rd day post-morphine suspension injection.
- Other 5-HT receptor antagonists, metergoline and mianserin, also reduced morphine tolerance.
Conclusions:
- The findings indicate that serotonin receptor modulation can impact morphine antinociception tolerance.
- A 5-HT2 receptor mechanism is implicated in the development of tolerance to morphine's pain-relieving effects.
- Targeting specific serotonin receptors may offer novel strategies to manage opioid tolerance.