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Role of receptor regulation in opioid tolerance mechanisms
1Department of Pharmacology, University of California Medical Center, San Francisco 94143.
Abstract:
The molecular basis of opioid tolerance/dependence has long eluded researchers, but recent advances in receptor regulation have suggested a useful conceptual approach to the problem. In NG108-15 neuroblastoma x glioma hybrid (NG) cells, opioid agonists inhibit adenylate cyclase in a dose-dependent, naloxone-antagonizable fashion. Chronic treatment with opioid agonists results in a series of molecular processes that, in a tolerance-like fashion, counteract this inhibition. These processes include desensitization and down-regulation of receptors and an increase in adenylate cyclase activity. Opioid inhibition of adenylate cyclase and opioid receptor down-regulation also have been observed in the brain. However, most studies have found that the receptors coupled to adenylate cyclase are not of the mu type, which are thought to be the primary mediators of opioid analgesia. Down-regulation has been observed for both mu and delta opioid receptors in the brain. However, in most cases, the time course of down-regulation is not correlated with that for tolerance development, and chronic morphine treatment does not result in down-regulation. Thus, opioid receptors in the brain, like those in NG cells, are subject to dynamic regulation by agonists, which probably has an important role in their function. However, it remains to be established that opioid receptor regulation is the basis of opioid tolerance and dependence.
Insights
Opioid agonists cause molecular changes like receptor desensitization and down-regulation, counteracting their inhibitory effects. While these processes occur in the brain, their direct link to opioid tolerance and dependence remains unproven.
Area of Science:
- Neuroscience
- Molecular Pharmacology
- Receptor Biology
Background:
- Opioid tolerance and dependence mechanisms are not fully understood.
- Opioid agonists inhibit adenylate cyclase in NG108-15 cells.
- Receptor regulation offers a potential framework for understanding opioid effects.
Purpose of the Study:
- To investigate the molecular basis of opioid tolerance and dependence.
- To examine opioid receptor regulation in response to chronic agonist treatment.
- To explore the role of adenylate cyclase and receptor dynamics.
Main Methods:
- Utilized NG108-15 neuroblastoma x glioma hybrid cells for experiments.
- Administered chronic opioid agonist treatment to observe cellular responses.
- Measured adenylate cyclase activity and receptor expression levels.
- Examined opioid receptor desensitization and down-regulation.
Main Results:
- Chronic opioid treatment led to receptor desensitization and down-regulation, counteracting initial adenylate cyclase inhibition.
- Opioid inhibition of adenylate cyclase and receptor down-regulation were observed in brain tissue.
- Receptors coupled to adenylate cyclase were often not mu-type.
- Down-regulation of mu and delta opioid receptors occurred in the brain, but timing often didn't correlate with tolerance.
Conclusions:
- Opioid receptors in the brain, similar to those in NG cells, undergo dynamic agonist-induced regulation.
- This dynamic regulation likely plays a significant role in opioid receptor function.
- It is not yet definitively established that opioid receptor regulation is the primary cause of opioid tolerance and dependence.