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533160 
Journal Article 
Different effects of opioid antagonists on mu-, delta-, and kappa-opioid receptors with and without agonist pretreatment 
Wang, DX; Sun, XC; Sadee, W 
2007 
Yes 
Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
EISSN: 1521-0103 
321 
2 
544-552 
English 
Opioid receptors display basal signaling ( constitutive, agonist-independent activity), which seems to be regulated by agonist exposure. Whereas agonist pretreatment desensitizes receptors to subsequent agonist stimulation, basal signaling of mu-opioid receptor ( MOR) was shown to increase. Moreover, agonist pretreatment converts the neutral antagonists naloxone and naltrexone into inverse agonists, suppressing basal signaling, whereas analogs with reduced C6- position, e. g., 6 beta-naltrexol, remain neutral antagonists at MOR under any condition. This study compares the regulation of basal signaling of MOR, delta-( DOR), and kappa-( KOR) opioid receptors after pretreatment with morphine or receptor- selective agonists, in transfected human embryonic kidney 293 cell membranes. Moreover, naloxone, naltrexone, and related antagonists were compared for binding potency and effect on basal and agonist- stimulated receptor signaling, measuring guanosine 5'-O-(3-[S-35] thio) triphosphate binding. The results demonstrate basal activity for each opioid receptor, which is modulated by pretreatment with agonists. Even closely related opioid antagonists display distinct patterns of neutral and inverse effects before and after agonist pretreatment, including distinct efficacies between naloxone and naltrexone at agonist- pretreated DOR and KOR. Pretreatment with different agonists has varying effects on inverse and neutral activities of some analogs tested. These results demonstrate that antagonist efficacy is context- dependent, possibly accounting for paradoxical pharmacological effects. Activity profiles at the three opioid receptors under different conditions could lead to antagonists with optimal clinical properties in treatment of addiction and adverse opioid effects. 
basal signaling activity; inverse agonist; antinociceptive tolerance; neutral antagonists; narcotic dependence; heavy drinkers; in-vivo; naltrexone; efficacy; mice