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Biochemical and behavioral studies on the interaction between mu- and kappa-opiate agonists in mice
S N Thorat1, Veeranna, P L Reddy
1Department of Pharmacodynamics, University of Illinois, Chicago 60612.
Abstract:
Male Swiss-Webster mice were rendered tolerant to morphine by subcutaneous implantation of a morphine pellet, each containing 75 mg morphine base, for 3 days. Mice implanted with placebo pellets served as controls. A high degree of tolerance to the analgesic effect of morphine developed as evidenced by decreased analgesic response to various doses of morphine. A selective kappa-opiate agonist, U-50,488H (8, 16 and 32 mg/kg, i.p.) produced dose-dependent analgesic and hypothermic effects in mice implanted with placebo pellets. A significant decrease in the analgesic and hypothermic effects of U-50,488H was observed in morphine tolerant mice as compared to placebo-treated mice. Mice were rendered tolerant to U-50,488H by injecting the drug (25 mg/kg, i.p.) twice daily for 4 days. Vehicle injected mice served as controls. Tolerance to the analgesic and hypothermic effects of U-50,488H in mice injected chronically with the drug was evidenced by the decreases in the intensity of these responses when compared to those observed in vehicle injected controls. Morphine produced a dose-dependent analgesic and hypothermic effects in mice injected chronically with vehicle but the intensity of these effects was significantly lower in mice injected chronically with U-50,488H. These results indicate that a substantial tolerance to analgesic and hypothermic effects of U-50,488H develops in morphine tolerant mice. The effect of chronic injections of U-50,488H on the binding of [3H]ethylketocyclazocine (EKC) and [3H]D-Ala2,MePhe4,Gly-ol5-enkephalin (DAMGO) to whole brain and spinal cord kappa- and mu-opiate receptors was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Morphine tolerance in mice significantly reduced the analgesic and hypothermic effects of the kappa-opiate agonist U-50,488H. Chronic U-50,488H also diminished morphine
Area of Science:
- Pharmacology
- Neuroscience
- Drug Tolerance
Background:
- Opioid analgesics like morphine are widely used for pain management.
- Developing tolerance to opioids can lead to reduced efficacy and increased side effects.
- Kappa-opiate agonists represent a distinct class of analgesics with potential therapeutic applications.
Purpose of the Study:
- To investigate the development of tolerance to the kappa-opiate agonist U-50,488H in morphine-tolerant mice.
- To examine the cross-tolerance between morphine and U-50,488H.
- To assess the impact of chronic U-50,488H administration on opiate receptor binding.
Main Methods:
- Induction of morphine tolerance via subcutaneous pellet implantation in Swiss-Webster mice.
- Administration of U-50,488H (a kappa-opiate agonist) to assess analgesic and hypothermic effects.
- Induction of U-50,488H tolerance through repeated intraperitoneal injections.
- Evaluation of morphine's effects in U-50,488H tolerant mice.
- Measurement of [3H]ethylketocyclazocine (EKC) and [3H]D-Ala2,MePhe4,Gly-ol5-enkephalin (DAMGO) binding to opiate receptors.
Main Results:
- Morphine-tolerant mice exhibited significantly decreased analgesic and hypothermic responses to U-50,488H.
- Chronic administration of U-50,488H led to tolerance in its own analgesic and hypothermic effects.
- Morphine's analgesic and hypothermic effects were significantly reduced in mice chronically treated with U-50,488H.
- Preliminary data suggests alterations in kappa- and mu-opiate receptor binding following chronic U-50,488H treatment.
Conclusions:
- Morphine tolerance is associated with substantial cross-tolerance to the kappa-opiate agonist U-50,488H.
- Chronic administration of U-50,488H induces tolerance to its own effects and also impacts morphine's efficacy.
- These findings highlight complex interactions between different opioid receptor systems in the development of tolerance.