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Withdrawal tolerance and unidirectional non-cross-tolerance in narcotic pellet-implanted mice
The Journal of Pharmacology and Experimental Therapeutics
|January 1, 1983
Summary
Mice developed significant tolerance to morphine, greater than to other opioids, demonstrating dispositional tolerance. They also showed withdrawal and homeostatic tolerance, indicating complex opioid adaptation mechanisms.
Area of Science:
- Pharmacology
- Neuroscience
- Toxicology
Background:
- Opioid tolerance is a complex phenomenon with various contributing factors.
- Understanding different types of tolerance is crucial for managing opioid use and withdrawal.
- Previous research indicated a unidirectional non-cross-tolerance effect with opioid pellet implantation.
Purpose of the Study:
- To investigate and differentiate multiple manifestations of opioid tolerance in mice.
- To characterize dispositional, withdrawal, and homeostatic tolerance to opioids.
- To explore the relationship between opioid tolerance and naloxone sensitivity.
Main Methods:
- Determined analgesic ED50 values for morphine, etorphine, heroin, and methadone in mice with etorphine pellets.
- Administered opioids subcutaneously (s.c.) and intracerebroventricularly (i.c.v.).
- Observed changes in ED50 values after pellet removal and during continuous pellet implantation.
Main Results:
- Greater tolerance (9-fold) was observed for morphine compared to other opioids (2- to 4-fold).
- Identified dispositional tolerance (s.c. vs. i.c.v. morphine), withdrawal tolerance (ED50 changes post-pellet removal), and homeostatic tolerance (normal sensitivity during pellet use).
- Homeostatic tolerance showed lability, potentially linked to altered naloxone sensitivity.
Conclusions:
- Opioid tolerance is multifaceted, involving dispositional, withdrawal, and homeostatic mechanisms.
- Homeostatic tolerance represents a physiological adaptation to chronic opioid exposure.
- The lability of homeostatic tolerance may influence precipitated withdrawal responses.