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Cellular and metabolic tolerance to an opioid narcotic in mouse brain
Abstract:
1. Running activity and brain levorphanol concentration were measured in nontolerant and tolerant mice given various doses of (3)H-levorphanol.2. The principal factor responsible for tolerance in the mouse is a loss of sensitivity to the narcotic drug at the cellular level in brain; despite adequate brain concentrations, the pharmacological effects are diminished or absent.3. There is also metabolic tolerance; a given dose establishes a lower brain concentration in tolerant than in non-tolerant animals.4. The two kinds of tolerance are distinguished here and the contribution of each is assessed.
Insights
Mice developed tolerance to levorphanol through reduced cellular sensitivity and lower brain drug concentrations. These two mechanisms, cellular and metabolic tolerance, were assessed to understand their contribution to the overall effect.
Area of Science:
- Pharmacology
- Neuroscience
- Toxicology
Background:
- Opioid tolerance is a significant challenge in pain management.
- Understanding the mechanisms of tolerance is crucial for developing effective analgesics.
- Levorphanol is a potent opioid analgesic with a complex tolerance profile.
Purpose of the Study:
- To investigate the mechanisms of levorphanol tolerance in mice.
- To differentiate between cellular and metabolic tolerance to levorphanol.
- To quantify the contribution of each tolerance mechanism.
Main Methods:
- Mice, both nontolerant and tolerant, were administered various doses of (3)H-levorphanol.
- Brain levorphanol concentrations were measured.
- Running activity was used as a proxy for pharmacological effect.
- The contribution of cellular and metabolic tolerance was assessed.
Main Results:
- Tolerance to levorphanol in mice is primarily due to a loss of cellular sensitivity in the brain.
- Despite adequate brain concentrations, pharmacological effects were diminished in tolerant mice.
- Metabolic tolerance also contributes, leading to lower brain levorphanol concentrations in tolerant animals compared to nontolerant ones.
Conclusions:
- Levorphanol tolerance involves both reduced cellular sensitivity and altered drug metabolism.
- Both mechanisms contribute to the diminished pharmacological effects observed in tolerant mice.
- Distinguishing these mechanisms is key to understanding opioid tolerance.