Ferulic acid-loaded nanostructure prevents morphine reinstatement: the involvement of dopamine system, NRF2, and ΔFosB in the striatum brain area of rats

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2023-07, Vol.396 (7), p.1535-1545
• Main Authors: Milanesi, Laura Hautrive, Rossato, Domenika Rubert, Rosa, Jéssica Leandra Oliveira, D’avila, Lívia Ferraz, Metz, Vinícia Garzella, Rampelotto, Camila Reck, Pereira, Viviane Gonçalves, Schaffazick, Scheila Rezende, de Bona da Silva, Cristiane, Burger, Marilise E.
• Format: Article
• Language: English
• Subjects: Addictions; Analgesics; Antioxidants; Bioavailability; Biomedical and Life Sciences; Biomedicine; Caudate-putamen; Dopamine; Dopamine D1 receptors; Dopamine D2 receptors; Dopamine D3 receptors; Dopamine transporter; Extinction behavior; Ferulic acid; Immunoreactivity; Lipid peroxidation; Mesolimbic system; Morphine; Neostriatum; Neuroprotection; Neurosciences; Neurotransmission; Oxidative stress; Pharmacology/Toxicology; Place preference conditioning; Reinstatement
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-023-02420-w

Morphine is among the most powerful analgesics and pain-relieving agents. However, its addictive properties limit their medical use because patients may be susceptible to abuse and reinstatement. Morphine addiction occurs because of dopamine release in the mesolimbic brain area, implying in an increase in oxidative stress. Ferulic acid (FA), a phenolic phytochemical found in a variety of foods, has been reported to exert antioxidant and neuroprotective effects; however, its low bioavailability makes its nano-encapsulated form a promising alternative. This study aimed to evaluate the protective effects of a novel nanosystem with FA on morphine reinstatement and the consequent molecular neuroadaptations and oxidative status in the mesolimbic region. Rats previously exposed to morphine in conditioned place preference (CPP) paradigm were treated with ferulic acid-loaded nanocapsules (FA-Nc) or nonencapsulated FA during morphine-preference extinction. Following the treatments, animals were re-exposed to morphine to induce the reinstatement. While morphine-preference extinction was comparable among all experimental groups, FA-Nc treatment prevented morphine reinstatement. In the dorsal striatum, while morphine exposure increased lipid peroxidation (LP) and reactive species (RS), FA-Nc decreased LP and FA decreased RS levels. Morphine exposure increased the dopaminergic markers (D1R, D3R, DAT) and ΔFosB immunoreactivity in the ventral striatum; however, FA-Nc treatment decreased D1R, D3R, and ΔFosB and increased D2R, DAT, and NRF2 . In conclusion, FA-Nc treatment prevented the morphine reinstatement, promoted antioxidant activity, and modified the dopaminergic neurotransmission, NRF2 , and ΔFosB, what may indicate a neuroprotective and antioxidant role of this nanoformulation.