Abstract
The inositol 1,4,5-trisphosphate (IP 3) content and intracellular free Ca 2+ ([Ca 2+] i) level in response to κ-opioid receptor stimulation with selective κ-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 IP 3 and [Ca 2+] i were increased following κ-opioid receptor stimulation. The responses of IP 3 and [Ca 2+] i to κ-opioid receptor stimulation were abolished in myocytes of rats that had received chronic injection of U50,488H for 4 days. κ-Opioid receptor stimulation with U50,488H also reduced the [Ca 2+] i transient, induced by electrical stimulation and caffeine, both known to mobilize [Ca 2+] i. The effect was abolished after the myocytes had been incubated with U50,488H at a subthreshold concentration for its effect on [Ca 2+] i for 24 h. The present study showed for the first time that, upon the development of tolerance to a κ-opioid receptor agonist, the responses of IP 3 and [Ca 2+] i to κ-opioid receptor stimulation were abolished. The lack of response in [Ca 2+] i was due to a failure of mobilization of Ca 2+ from its intracellular pool. Further study is needed to determine the events that occur after the κ-opioid receptor stimulation to production of IP 3 upon the development of tolerance to a κ-opioid.
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