ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
This article is part of the Research TopicExploring the Interplay Between Stress, Neuropeptides, and Alcohol Use DisorderView all articles
Functional interaction between orexin/dynorphin transmission in the posterior paraventricular nucleus of the thalamus following alcohol dependence: mediation of alcohol-seeking behavior
Provisionally accepted
- 1California State University San Marcos, San Marcos, United States
- 2The Scripps Research Institute, San Diego, United States
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Stress is a major contributor to the chronic nature of alcohol use disorder (AUD). Orexin (OX) neurons project to the paraventricular nucleus of the thalamus (PVT)—particularly the posterior part (pPVT)— a structure that plays a key role in stress regulation. The blockade of OX receptors in the pPVT was shown to prevent the stress-induced reinstatement of alcohol seeking in alcohol-dependent rats. Accumulating evidence indicates interactions among OX and dynorphin (DYN) in the pPVT, but unclear is the role of OX and DYN transmission in the pPVT in the stress-induced alcohol seeking during alcohol abstinence. Male Wistar rats were trained to self-administer 10% alcohol for 3 weeks. They then underwent 6 weeks of chronic intermittent alcohol vapor exposure to induce dependence. After 12 extinction sessions (~3 weeks of abstinence), the rats received intra-pPVT infusions of the dual OX receptor antagonist TCS1102 (15 µg/0.5 µl), the κ-opioid receptor (KOP) antagonist nor-binaltorphimine (norBNI; 4 µg/0.5 µl), or their combination, and they were assessed for their reactivity to the stress (footshock)- induced reinstatement of alcohol-seeking behavior. In dependent rats, TCS1102 and norBNI reduced reinstatement but, when co-administered, their individual effects were modulated. At the time of testing, increases in Hcrt and Pdyn mRNA expression in the hypothalamus and a decrease in Hcrtr1 expression and an increase in Oprk1 expression in the pPVT were observed. These findings reveal a functional interaction among OX receptor and KOP signaling in the pPVT that underlies relapse that is precipitated by stress post-dependence, underscoring the value of multi-target interventions to restore pPVT function and prevent relapse.
Keywords: alcohol dependence, alcohol-seeking behavior, Orexin (hypocretin), dynorphin, orexin receptors 1 and 2, Kappa opioid receptor (KOR)
Received: 04 Oct 2025; Accepted: 18 Nov 2025.
Copyright: © 2025 Flores-Ramirez, Pascasio and Martin-Fardon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Francisco J Flores-Ramirez, ffloresramir@csusm.edu
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