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Chronic U50,488H abolishes inositol 1,4,5-trisphosphate and intracellular Ca2+ elevations evoked by kappa-opioid
1Department of Physiology, Faculty of Medicine, University of Hong Kong, Hong Kong.
Abstract:
The inositol 1,4,5-trisphosphate (IP3) content and intracellular free Ca2+ ([Ca2+]i) level in response to kappa-opioid receptor stimulation with selective kappa-opioid receptor agonists, dynorphin-(1-13) and trans-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeacetamidel (U50,488H) were determined in ventricular myocytes. Both IP3 and [Ca2+]i were increased following kappa-opioid receptor stimulation. The responses of IP3 and [Ca2+]i to kappa-opioid receptor stimulation were abolished in myocytes of rats that had received chronic injection of U50,488H for 4 days. kappa-Opioid receptor stimulation with U50,488H also reduced the [Ca2+]i transient, induced by electrical stimulation and caffeine, both known to mobilize [Ca2+]i. The effect was abolished after the myocytes had been incubated with U50,488H at a subthreshold concentration for its effect on [Ca2+]i for 24 h. The present study showed for the first time that, upon the development of tolerance to a kappa-opioid receptor agonist, the responses of IP3 and [Ca2+]i to kappa-opioid receptor stimulation were abolished. The lack of response in [Ca2+]i was due to a failure of mobilization of Ca2+ from its intracellular pool. Further study is needed to determine the events that occur after the kappa-opioid receptor stimulation to production of IP3 upon the development of tolerance to a kappa-opioid.
Insights
Kappa-opioid receptor stimulation increases inositol 1,4,5-trisphosphate (IP3) and intracellular calcium ([Ca2+]i). Tolerance to kappa-opioid agonists abolishes these responses, indicating a failure in intracellular calcium mobilization.
Area of Science:
- Pharmacology
- Cardiology
- Cell Biology
Background:
- Kappa-opioid receptors are involved in cardiovascular regulation.
- Inositol 1,4,5-trisphosphate (IP3) and intracellular calcium ([Ca2+]i) play crucial roles in myocyte function.
- Understanding opioid receptor signaling is vital for cardiovascular research.
Purpose of the Study:
- To investigate the effects of kappa-opioid receptor stimulation on IP3 and [Ca2+]i in ventricular myocytes.
- To determine if tolerance to kappa-opioid agonists affects these responses.
- To elucidate the mechanisms underlying altered calcium mobilization.
Main Methods:
- Ventricular myocytes were stimulated with kappa-opioid receptor agonists (dynorphin-(1-13) and U50,488H).
- Inositol 1,4,5-trisphosphate (IP3) and intracellular free Ca2+ ([Ca2+]i) levels were measured.
- Tolerance was induced via chronic U50,488H injection or prolonged incubation.
- Calcium transients were measured using electrical stimulation and caffeine.
Main Results:
- Kappa-opioid receptor stimulation increased both IP3 and [Ca2+]i.
- These responses were abolished in myocytes from rats with chronic U50,488H exposure.
- Tolerance to U50,488H also inhibited [Ca2+]i transients induced by electrical stimulation and caffeine.
- Prolonged incubation with U50,488H also abolished the responses.
Conclusions:
- Tolerance to kappa-opioid receptor agonists prevents IP3 and [Ca2+]i increases.
- The lack of [Ca2+]i response is due to impaired intracellular calcium release.
- Further research is needed to identify the specific molecular events leading to tolerance in this pathway.