Kappa opioid receptors (KORs) in the anterior paraventricular nucleus of the thalamus (aPVT) mediate morphine withdrawal-, anxiety-, fear-, and KOR agonist-induced aversion-like behaviors in mice

This preprint localizes kappa opioid receptor (OPRK1) control of aversion, anxiety, and morphine withdrawal to anterior paraventricular thalamus neurons, showing that conditional KOR knockdown reduces these behaviors in mice. The Claidex record for OPRK1 holds one indexed failure, the KOR antagonist aticaprant, which did not separate from placebo on anhedonia in major depressive disorder in the VENTURA program (aticaprant-oprk1-mdd-anhedonia-ventura-phase3-efficacy-failure). The preprint supports a real role for KOR in aversive and stress behaviors, and it also points to why systemic antagonism may underdeliver in depression, because the behavioral effects were circuit-specific and partly sex-specific, with conditioned aversion reduced only in males. A target that acts through defined thalamic circuits and sex-dependent outputs is a poor match for an unenriched systemic antagonist tested on a broad anhedonia endpoint, which is the setting the indexed failure used.