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Opioid receptor upregulation and supersensitivity in mice: effect of morphine sensitivity
B C Yoburn1, S P Kreuscher, C E Inturrisi
1Department of Pharmaceutical Sciences, College of Pharmacy & Allied Health Professions, St. John's University, Jamaica, NY 11439.
Abstract:
Mice of the Swiss-Webster strain obtained from two suppliers (Taconic, Charles River) were found to differ in their sensitivity to morphine. Mice from Taconic were approximately two-fold more sensitive to the analgesic and lethal effects of morphine compared to the Charles River mice. In a third strain, C3H/HEN, morphine was found to be more than 2.5 times more potent in producing analgesia than in the Charles River mice. Binding studies showed that the Taconic mice and C3H/HEN mice had approximately 40% and 60%, respectively, more specific [3H]naloxone binding sites in brain than did the less sensitive Charles River mice. When treated with chronic naltrexone for 8 days the analgesic potency of morphine was increased by approximately 90% for both Swiss-Webster mice and by 20% for the C3H/HENs. [3H]Naloxone binding was increased by 45-50% in the Swiss-Webster strains, but by only 33% in C3H/HEN mice. These data indicate that receptor upregulation is directly related to increases in morphine potency. Further, these findings suggest that initial sensitivity to morphine can determine the degree of functional supersensitivity and relative receptor upregulation produced by chronic opioid antagonist treatment.
Insights
Mice show varying sensitivity to morphine based on supplier and strain. Initial sensitivity influences how opioid antagonist treatment affects morphine potency and receptor levels.
Area of Science:
- Pharmacology
- Neuroscience
- Genetics
Background:
- Mouse strain and supplier can influence drug response.
- Opioid receptor sensitivity varies, impacting drug efficacy.
Purpose of the Study:
- To investigate the relationship between initial morphine sensitivity and opioid receptor upregulation.
- To compare morphine potency and naloxone binding across different mouse strains and suppliers.
Main Methods:
- Assessed morphine analgesic and lethal effects in Swiss-Webster (Taconic, Charles River) and C3H/HEN mice.
- Quantified specific [3H]naloxone binding sites in mouse brains.
- Administered chronic naltrexone and re-evaluated morphine potency and binding.
Main Results:
- Taconic Swiss-Webster mice were more sensitive to morphine than Charles River mice.
- C3H/HEN mice showed higher morphine potency and greater [3H]naloxone binding than Charles River mice.
- Chronic naltrexone increased morphine potency and [3H]naloxone binding, with varying degrees based on initial sensitivity.
Conclusions:
- Receptor upregulation correlates directly with increased morphine potency.
- Initial morphine sensitivity predicts the extent of functional supersensitivity and receptor upregulation following chronic opioid antagonist treatment.