PMID: 8967989Dec 1, 1996Paper

Inverse agonistic effect of ICI-174,864 on the cloned delta-opioid receptor: role of G protein and adenylyl cyclase activation

Molecular Pharmacology
T T ChiuY H Wong

Abstract

Previous studies have established that the delta-selective antagonist ICI-174,864 exhibits negative intrinsic activity at the delta-opioid receptors in NG108-15 membranes. To determine whether ICI-174,864 can function as a true inverse agonist in intact cells, its ability to stimulate cAMP accumulation was examined in a human embryonic kidney 293 cell line (293/DOR) expressing the cloned murine delta-opioid receptor. Forskolin-stimulated cAMP accumulation in the 293/DOR cells was dose-dependently suppressed by the delta-selective agonist [D-Pen2, D-Pen5]enkephalin, and such inhibition was abolished by pertussis toxin or the opiate antagonist naloxone. In contrast, ICI-174,864 significantly potentiated the forskolin response. The ICI-174,864-induced enhancement of the forskolin response exhibited dose-dependency and was antagonized by [D-Pen2,D-Pen5]enkephalin and blocked by pertussis toxin. Neither ICI-174,864 nor pertussis toxin elevated the basal level of cAMP accumulation in the absence of forskolin. Other opiate antagonists, such as naloxone and naltrindole, were ineffective in enhancing the forskolin-stimulated cAMP accumulation. Elevation of cAMP levels in response to the activation of Gs (through either ligand-bound rece...Continue Reading

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