Related Experiment Videos
Selective tolerance at mu and kappa opioid receptors modulating norepinephrine release in guinea pig cortex
L L Werling1, P N McMahon, B M Cox
1Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Abstract:
The development of selective tolerance, that is, a loss in the ability of an agonist to exert an effect without concomitant loss in the ability of an agonist which acts through another receptor type to similarly lose its effectiveness, has provided supporting evidence for the existence of multiple opioid receptor types in brain and peripheral tissues. In brain, this phenomenon has generally been demonstrated for agonists which produce different physiological effects. In this study, we describe selective tolerance at two opioid receptor types which converge upon a single function. The effects of chronic treatment for 6 days with the mu agonist morphine (1.7 mg/kg/hr) and the kappa agonist U50, 488H (300 micrograms/kg/hr) on the ability of mu and kappa opioid agonists to inhibit the stimulated release of [3H]norepinephrine from slices of guinea pig cortex were investigated. Mu, delta and kappa selective agonists have been shown previously to be capable of regulating the stimulated release of norepinephrine. Chronic administration of morphine resulted in a diminution in the ability of the mu agonists Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol, morphine and etorphine, but not of U50, 488H, to inhibit the stimulated release of [3H]norepinephrine. Conversely, chronic U50, 488H infusion decreased the ability of U50, 488H to inhibit release, with no change in the effectiveness of Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol. The degree of tolerance observed for mu agonists in tissue from morphinized animals is discussed with regard to their efficacy and selectivity.
Insights
Selective tolerance demonstrates distinct opioid receptor types. Chronic morphine treatment impaired mu-opioid agonists, while U50,488H affected kappa-opioid agonists, confirming receptor-specific desensitization.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Selective tolerance, a differential loss of agonist efficacy, supports multiple opioid receptor types.
- Previous studies demonstrated this phenomenon for agonists acting on different receptor types or producing distinct physiological effects.
Purpose of the Study:
- To investigate selective tolerance at two opioid receptor types (mu and kappa) that converge on a single function.
- To examine the effects of chronic morphine and U50,488H treatment on opioid agonist-induced inhibition of norepinephrine release.
Main Methods:
- Chronic administration of the mu agonist morphine or the kappa agonist U50,488H to guinea pigs for 6 days.
- Measurement of the ability of various mu and kappa opioid agonists to inhibit stimulated [3H]norepinephrine release from guinea pig cortical slices.
Main Results:
- Chronic morphine treatment led to tolerance to mu-opioid agonists (Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol, morphine, etorphine) but not the kappa agonist U50,488H.
- Chronic U50,488H infusion induced tolerance to itself (kappa agonist) but did not affect the efficacy of the mu agonist Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol.
Conclusions:
- These findings provide evidence for receptor-selective tolerance at mu and kappa opioid receptors.
- This selective desensitization occurs even when both receptor types modulate the same cellular function, such as norepinephrine release.