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Dissociation of mu opioid tolerance from receptor down-regulation in rat spinal cord
1Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.
Abstract:
The effect of continuous intrathecal infusions of opioids was studied in rats. Chronic intrathecal infusion of the highly selective mu agonist, [NMPhe3, D-Pro4]morphiceptin produced a rapid onset of tolerance to the drug in the analgesic test. However, membrane prepared from the spinal cords of the rats chronically infused with a low dose of the drug showed no statistically significant change in the number of mu or delta receptor binding sites. In addition, membrane prepared from rats challenged with a single high-dose bolus injection of [NMPhe3, D-Pro4]morphiceptin did not produce alterations in the receptor binding number. If the chronically treated rats were challenged with an acute bolus dose of [NMPhe3, D-Pro4]morphiceptin, there was a significant decrease in the number of binding sites. The reduced binding site number was observed for the mu ligand but not for the delta ligand. A similar decrease of receptor binding can also be achieved by chronic infusion of the drug at high doses. Scatchard plot showed a decrease of maximum mu binding sites in the membranes prepared from the combined chronic infusion-acute injection treated rats. Brain tissue from the same rats showed no change in the number of mu and delta receptor binding sites, indicating that the down-regulation of mu receptors was confined to the spinal cord only. Morphine did not induce receptor down-regulation by acute, chronic or combined treatments. These results suggest that in the rat spinal cord, tolerance can be induced without apparent receptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Chronic intrathecal opioid administration in rats induced tolerance without significant changes in mu or delta receptor binding sites. However, acute challenge after chronic infusion caused a decrease in mu receptor binding in the spinal cord.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Continuous intrathecal infusions of opioids are used to manage pain.
- Opioid tolerance, a decrease in drug efficacy over time, is a significant clinical challenge.
- The relationship between opioid tolerance and receptor binding site density, particularly mu and delta receptors, requires further investigation.
Purpose of the Study:
- To investigate the effects of chronic intrathecal [NMPhe3, D-Pro4]morphiceptin infusion on opioid receptor binding in rats.
- To determine if tolerance to [NMPhe3, D-Pro4]morphiceptin is associated with changes in mu and delta receptor density in the spinal cord.
- To compare the effects of [NMPhe3, D-Pro4]morphiceptin with morphine on receptor down-regulation.
Main Methods:
- Rats received continuous intrathecal infusions of [NMPhe3, D-Pro4]morphiceptin at low or high doses.
- Receptor binding assays were performed on spinal cord and brain tissue membranes.
- Scatchard analysis was used to quantify changes in receptor binding site maximum (Bmax).
Main Results:
- Chronic low-dose [NMPhe3, D-Pro4]morphiceptin infusion led to rapid analgesic tolerance without altering mu or delta receptor binding sites.
- Acute challenge with [NMPhe3, D-Pro4]morphiceptin in chronically treated rats significantly decreased mu, but not delta, receptor binding sites in the spinal cord.
- High-dose chronic infusion or combined chronic infusion-acute challenge also reduced mu receptor binding, specifically in the spinal cord; brain tissue showed no changes. Morphine did not induce receptor down-regulation.
Conclusions:
- Tolerance to [NMPhe3, D-Pro4]morphiceptin in the rat spinal cord can occur without a significant decrease in overall mu or delta receptor binding sites.
- Acute administration of [NMPhe3, D-Pro4]morphiceptin can induce a selective down-regulation of mu receptors in the spinal cord following chronic exposure.
- These findings suggest that opioid tolerance mechanisms may involve processes beyond simple receptor number reduction in the spinal cord.