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Receptor-selective changes in mu-, delta- and kappa-opioid receptors after chronic naltrexone treatment in mice
Heidi M B Lesscher1, Alexis Bailey, J Peter H Burbach
1Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Center Utrecht, The Netherlands.
Abstract:
Chronic treatment with the opioid antagonist naltrexone induces functional supersensitivity to opioid agonists, which may be explained by receptor up-regulation induced by opioid receptor blockade. In the present study, the levels of opioid receptor subtypes through the brain of mice were determined after chronic naltrexone treatment using quantitative in vitro autoradiography. This is the first complete mapping study in mice for micro-, delta- and kappa-opioid receptors after chronic naltrexone exposure. Treatment with naltrexone clearly induced up-regulation of micro- (mean 80%) and, to a lesser extent, delta-opioid receptors (mean 39%). The up-regulation of micro- and delta-opioid receptors was evident throughout the brain, although there was variation in the percentage change across brain regions. In contrast, consistent up-regulation of kappa-opioid receptors was observed in cortical structures only and was not so marked as for micro- and delta-opioid receptors. In noncortical regions kappa-opioid receptor expression was unchanged. Taken together, the present findings suggest opioid receptor subtype-selective regulation by chronic naltrexone treatment in mice.
Insights
Chronic naltrexone treatment up-regulates micro- and delta-opioid receptors throughout the mouse brain. Kappa-opioid receptors showed limited up-regulation in cortical areas, indicating subtype-selective regulation.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Chronic opioid antagonist treatment, like naltrexone, can lead to functional supersensitivity to opioid agonists.
- This phenomenon is hypothesized to result from receptor up-regulation caused by opioid receptor blockade.
Purpose of the Study:
- To investigate the effects of chronic naltrexone treatment on opioid receptor subtype levels in the mouse brain.
- To provide the first comprehensive mapping of micro-, delta-, and kappa-opioid receptors following chronic naltrexone exposure in mice.
Main Methods:
- Quantitative in vitro autoradiography was employed to measure opioid receptor subtype levels.
- Brain tissue from mice subjected to chronic naltrexone treatment was analyzed.
Main Results:
- Naltrexone treatment significantly up-regulated micro-opioid receptors (mean 80%) and delta-opioid receptors (mean 39%) across the brain.
- Up-regulation of micro- and delta-opioid receptors varied in percentage across different brain regions.
- Kappa-opioid receptors showed consistent, but less pronounced, up-regulation in cortical regions only; noncortical levels remained unchanged.
Conclusions:
- Chronic naltrexone administration induces opioid receptor subtype-selective regulation in the mouse brain.
- The findings suggest differential adaptive responses of micro-, delta-, and kappa-opioid receptors to sustained blockade by naltrexone.
