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Opioid antagonist-induced receptor upregulation: effects of concurrent agonist administration
B C Yoburn1, A Duttaroy, S Shah
1Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439.
Abstract:
The present study examined whether opioid antagonist-induced receptor upregulation could be antagonized by simultaneous treatment with opioid agonists. Mice were treated concurrently with opioid agonists (morphine, fentanyl, etorphine) and antagonists (naloxone, naltrexone) over a period of 7-8 days. Concurrent morphine (1 or 4, 75 mg SC implanted pellets), fentanyl (5.0 mg/kg/day, infusion) or etorphine (0.25 mg/kg/day, infusion) administration were unable to inhibit upregulation of mu opioid (DAMGO) receptors by either naloxone (1 mg/kg/day, infusion) or naltrexone (15 mg or 2 mg SC implanted pellet). Only a very high infusion dose of etorphine (10 mg/kg/day) inhibited upregulation by naltrexone (2mg SC implanted pellet). These results indicate that antagonist-induced upregulation is a robust, receptor-mediated phenomenon.
Insights
Opioid antagonists cause receptor upregulation, which cannot be blocked by most opioid agonists. This indicates that antagonist-induced receptor changes are a strong, receptor-mediated effect.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opioid receptors are critical targets for pain management.
- Opioid antagonists can induce receptor upregulation.
- The interaction between agonists and antagonists in receptor modulation is not fully understood.
Purpose of the Study:
- To investigate if opioid agonists can prevent opioid antagonist-induced receptor upregulation.
- To determine the robustness of antagonist-induced mu opioid receptor (DAMGO) upregulation.
Main Methods:
- Mice were treated with opioid agonists (morphine, fentanyl, etorphine) and antagonists (naloxone, naltrexone) concurrently for 7-8 days.
- Various administration routes and doses were used, including subcutaneous pellets and daily infusions.
- Mu opioid receptor (DAMGO) levels were assessed to quantify upregulation.
Main Results:
- Concurrent administration of morphine, fentanyl, or low-dose etorphine did not inhibit naloxone- or naltrexone-induced mu opioid receptor upregulation.
- A very high dose of etorphine (10 mg/kg/day) was required to inhibit naltrexone-induced upregulation.
- These findings highlight the resilience of antagonist-induced receptor upregulation.
Conclusions:
- Opioid antagonist-induced receptor upregulation is a potent phenomenon.
- This upregulation is primarily receptor-mediated and difficult to antagonize with simultaneous agonist treatment.
- The results suggest that the receptor system robustly responds to antagonist exposure.