TY - JOUR T1 - Duration of Action of a Broad Range of Selective Kappa Opioid Receptor Antagonists is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.074195 SP - mol.111.074195 AU - Erica J Melief AU - Mayumi Miyatake AU - F. Ivy Carroll AU - Cecile Beguin AU - William A Carlezon AU - Bruce M Cohen AU - Sarah Grimwood AU - Charles Mitch AU - Linda M Rorick-Kehn AU - Charles Chavkin Y1 - 2011/01/01 UR - http://molpharm.aspetjournals.org/content/early/2011/08/10/mol.111.074195.abstract N2 - The kappa opioid receptor is a widely expressed G-Protein Coupled Receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective kappa opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal Kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57Bl/6 wild type mice to determine the durations of antagonist action of novel kappa opioid receptor ligands and examined their efficacies for JNK1 activation as compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation (RTI-5989-97; RTI-5989-194; RTI-5989-241; norBNI; JDTic), and 7 had short durations of action and did not increase phospho-JNK-ir (RTI-5989-212; RTI-5989-240; JSPA0658; JSPA071B; PF4455242; FP3FBZ; naloxone). Following long acting antagonist treatment, pJNK-ir did not increase in mice lacking the kappa opioid receptor; increased pJNK-ir returned to baseline by 48 hr after treatment; and a second challenge with norBNI 72 hr following the first did not increase pJNK-ir. Long lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule kappa opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the kappa receptor does not require sustained JNK activation. ER -