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Differentiation of spinal and supraspinal opioid receptors by morphine tolerance
B C Yoburn1, K Lutfy, S Azimuddin
1Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439.
Abstract:
Mice treated for 72 hrs with morphine (subcutaneously implanted pellets) were tested with a variety of opioid receptor agonists to examine the development of tolerance and cross-tolerance to their analgesic action. The development of spinal and supraspinal tolerance following morphine treatment was evaluated by administering compounds systemically (sc), intrathecally (IT) and intracerebroventricularly (ICV). Following morphine treatment, tolerance to morphine analgesia was observed following IT, ICV and sc administration. Chronic morphine treatment also produced cross-tolerance to the analgesic effects of the selective delta opioid receptor agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) following IT and ICV administration. However, morphine treatment selectively produced cross-tolerance to ICV [D-Ala2, NMePhe4, Gly-ol5]enkephalin (DAGO) (mu receptor agonist) analgesia, without altering IT DAGO analgesia. These results suggest that brain and spinal cord receptors mediating the effects of DAGO differ in terms of the development of cross-tolerance to morphine; and suggest that tolerance to systemic morphine may be due to changes in spinal delta and brain mu and delta receptor mechanisms.
Insights
Mice developed tolerance to morphine
Area of Science:
- Pharmacology
- Neuroscience
Background:
- Opioid medications like morphine are widely used for pain relief.
- Understanding the development of tolerance is crucial for effective pain management.
Purpose of the Study:
- To investigate the development of tolerance and cross-tolerance to morphine's analgesic effects.
- To explore differences in tolerance mechanisms between spinal and supraspinal opioid receptors.
Main Methods:
- Mice received chronic morphine treatment via subcutaneous pellets for 72 hours.
- Analgesic effects were tested using various opioid receptor agonists administered systemically, intrathecally (IT), and intracerebroventricularly (ICV).
- Tolerance and cross-tolerance were evaluated based on reduced analgesic responses.
Main Results:
- Morphine treatment led to tolerance to its own analgesic effects via IT, ICV, and systemic routes.
- Cross-tolerance to a delta opioid receptor agonist (DPDPE) was observed after IT and ICV administration.
- Selective cross-tolerance to a mu opioid receptor agonist (DAGO) occurred only with ICV administration, not IT.
Conclusions:
- Opioid receptor mechanisms in the brain and spinal cord differ in developing cross-tolerance to morphine.
- Tolerance to systemic morphine may involve changes in spinal delta and brain mu/delta opioid receptor pathways.