• Hafez Yadi, Bahareh Soleimanpourian, Shayan Gooran, Amirhossein Momeni, Nourollah Rezaei, Ali Siahposht-Khachaki, and Saeid Bagheri-Mohammadi.
• Student Research Committee Mazandaran University of Medical Sciences Sari Iran; Universal Scientific Education and Research Network (USERN) Tehran Iran.
• Neuroscience. 2025 Feb 1; 569: 213121-31.

BackgroundBehavior in both humans and animals is significantly influenced by the brain's reward system. Many studies have shown that this dopaminergic system is the root of drug addiction and abuse. Melatonin, an indoleamine neurohormone, has been studied for its potential negative effects on addictive drugs such as morphine. This study evaluates the effect of intraventricular melatonin injection during different phases of morphine conditioning.MethodRats were conditioned with morphine [5 mg/kg; subcutaneously (SC)] for three days. The changes in conditioned place preference (CPP) scores following the injection of different doses of melatonin [25, 50, and 100 μg/kg; intracerebroventricular (ICV)] were investigated during the acquisition, expression, extinction, and reinstatement phases of morphine conditioning. After completing these steps, the c-Fos level in the nucleus accumbens (NAc) was measured using the ELISA technique.ResultThe results indicated that daily injections of 50 and 100 μg/kg melatonin during the acquisition and expression phases caused a dose-dependent decrease in the conditioning score. During the extinction phase, melatonin administration reduced its duration incrementally. Notably, only the 100 μg/kg dose significantly decreased morphine reinstatement. In terms of c-Fos levels, which were elevated after morphine consumption, melatonin administration led to a significant reduction across all phases.ConclusionThis study demonstrates the neural interaction between melatonin and the opioid system. The evidence suggests that melatonin may be effective at decreasing drug-related rewards and has potential utility in preventing addiction.Copyright © 2025 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.

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