Nociceptin orphanin F/Q Pathways are dysregulated by stress and modulate reward responsiveness and motivated behavior across species
Source: Molecular psychiatry
Authors: Diego A Pizzagalli, Meghan Gallo, Michael T Treadway, Brian D Kangas, Jocelyn Breton, Michael R Bruchas, Ann M Graybiel, Emily Hueske, Kevin G Bath, Publication Date: Sat, 19 Sep 2026 06:00:00 -0400
Mol Psychiatry. 2026 Sep 19. doi: 10.1038/s41380-026-03898-5. Online ahead of print.
ABSTRACT
Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has antidepressant/anti-anhedonic effects. However, the mechanisms underlying reward-related effects remain unclear. Here, we investigated the role of NOPR in a broad spectrum of reward-related phenotypes (reward consumption, reward learning, motivated behavior) alongside potentially prohedonic effects of NOPR antagonism across species. Study 1 evaluated whether exposure to early-life adversity upregulated ventral tegmental area (VTA) and striatal prepronociceptin (Pnoc) gene expression in adult mice. Study 2 assessed whether NOPR antagonism boosted reward learning in rats using the touchscreen-based Probabilistic Reward Task. Finally, Study 3 tested whether NOPR antagonism modulated decision about motivated behavior using the Effort Expenditure for Reward Task among depressed humans. In Study 1, early-life adversity induced reduced sucrose preference and produced enduring and sex-dependent alterations in effort-related reward behavior, and increased Pnoc expression in the VTA; in females (but not males), early-life adversity increased Pnoc expression in the dorsal striatum. In Study 2, acute administration of 30 mg/kg (but not lower doses) of a NOPR antagonist (BTRX-246040) enhanced reward learning in rats. Finally, in Study 3, relative to placebo, 8-week treatment with BTRX-246040 modulated choice consistency during a motivated task in depressed humans. Collectively, our findings indicate that chronic stress alters Pnoc and mRNA levels of Pnoc-expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows promising efficacy in increasing reward-related behaviors in rodents and humans. Future studies using similar manipulations and outcome measures across species are warranted.
PMID:42763342 | DOI:10.1038/s41380-026-03898-5
Pubmed ID: pubmed:42763342
Identifiers: pmid:42763342, doi:10.1038/s41380-026-03898-5,
Paper chosen by Rajesh Khanna
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Pizzagalli et al. studied the nociceptin receptor (NOPR) and reward in mice, rats and humans. In mice, early-life adversity reduced sucrose preference and raised Pnoc expression in the VTA, and in the dorsal striatum of females only. In rats, a high dose of the NOPR antagonist BTRX-246040 improved reward learning. In depressed patients, eight weeks of the drug changed choice consistency on an effort task compared with placebo. That is a less clear-cut result than the animal findings.
Why should you care? Anhedonia, the loss of pleasure, is common in depression, and current drugs treat it poorly. NOPR antagonists could target it directly.