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Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats.


ABSTRACT: BACKGROUND:New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical kappa opioid receptor antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particularly in tests to establish safety. This study was designed to test dose- and time-course effects of novel kappa opioid receptor antagonists with the goal of identifying short-acting lead compounds for future medication development. METHODS:We screened 2 novel, highly selective kappa opioid receptor antagonists (CYM-52220 and CYM-52288) with oral efficacy in the warm water tail flick assay in rats to determine initial dose and time course effects. For comparison, we tested existing kappa opioid receptor antagonists JDTic and LY-2456302 (also known as CERC-501 or JNJ-67953964). RESULTS:In the tail flick assay, the rank order of duration of action for the antagonists was LY-2456302?

SUBMITTER: Page S 

PROVIDER: S-EPMC7145521 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Behavioral Pharmacology of Novel Kappa Opioid Receptor Antagonists in Rats.

Page Sarah S   Mavrikaki Maria M MM   Lintz Tania T   Puttick Daniel D   Roberts Edward E   Rosen Hugh H   Carroll F Ivy FI   Carlezon William A WA   Chartoff Elena H EH  

The international journal of neuropsychopharmacology 20191101 11


<h4>Background</h4>New treatments for stress-related disorders including depression, anxiety, and substance use disorder are greatly needed. Kappa opioid receptors are expressed in the central nervous system, including areas implicated in analgesia and affective state. Although kappa opioid receptor agonists share the antinociceptive effects of mu opioid receptor agonists, they also tend to produce negative affective states. In contrast, selective kappa opioid receptor antagonists have antidepre  ...[more]

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