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Simultaneous development of opioid tolerance and opioid antagonist-induced receptor upregulation
B C Yoburn1, V Sierra, K Lutfy
1Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439.
Abstract:
Mice treated chronically with opioid antagonists have increased receptor density in brain and are supersensitive to the pharmacodynamic action of morphine. In the present study mice were implanted subcutaneously with naltrexone or placebo pellets for 8 days. During implantation mice received daily injections of morphine (100 or 250 mg/kg) or saline. Morphine analgesia was completely blocked in mice that were implanted with naltrexone at the low dose of morphine; while some analgesic action was observed at the higher dose. Mice implanted with placebo were analgesic following the daily morphine treatment. At the end of 8 days the pellets were removed and 24 h later some mice were tested for morphine analgesia while others were examined in binding studies. Naltrexone treatment increased [3H]naloxone, 3H[D-Ala2-D-Leu5]enkephalin (DADLE) and 3H[D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO) binding compared to controls and increased the analgesic potency of morphine. Daily treatment with morphine did not alter brain opioid binding or naltrexone-induced receptor upregulation. Mice injected daily with morphine were significantly less sensitive to morphine (tolerant) than their respective saline control group for both the placebo and the naltrexone-treated groups. However, naltrexone-treated mice were more sensitive to morphine than placebo controls regardless of whether they were injected daily with morphine or not. These results indicate that if naltrexone-induced opioid receptor upregulation occurs in the presence of repeated agonist administration, the new binding sites mediate tolerance via desensitization to morphine.
Insights
Opioid antagonists like naltrexone upregulate opioid receptors, increasing sensitivity to morphine. However, chronic morphine administration leads to tolerance, with new naltrexone-induced receptors mediating this effect through desensitization.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Chronic opioid antagonist administration in mice leads to increased brain opioid receptor density and supersensitivity to morphine.
- Opioid receptor upregulation is a known compensatory mechanism in the brain.
Purpose of the Study:
- To investigate the effects of naltrexone-induced opioid receptor upregulation in the presence of chronic morphine administration on morphine analgesia and receptor binding.
- To determine if naltrexone-induced receptor upregulation influences morphine tolerance.
Main Methods:
- Mice were subcutaneously implanted with naltrexone or placebo pellets for 8 days.
- During implantation, mice received daily injections of morphine (100 or 250 mg/kg) or saline.
- Following pellet removal, morphine analgesia and opioid receptor binding ([3H]naloxone, DADLE, DAGO) were assessed.
Main Results:
- Naltrexone treatment increased opioid receptor binding and the analgesic potency of morphine.
- Daily morphine injections induced tolerance, reducing sensitivity to morphine's analgesic effects.
- Naltrexone-treated mice exhibited greater sensitivity to morphine compared to placebo controls, irrespective of daily morphine treatment.
- Chronic morphine administration did not affect brain opioid binding or naltrexone-induced receptor upregulation.
Conclusions:
- Naltrexone-induced opioid receptor upregulation, even with concurrent chronic morphine administration, results in increased morphine sensitivity.
- The newly upregulated opioid receptors appear to mediate tolerance through desensitization when exposed to repeated agonist administration.
- These findings elucidate the complex interplay between opioid receptor regulation and the development of tolerance.