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

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Abstract

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.

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Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001. This study is part of the National Institute of Science and Technology in Pharmaceutical Nanotechnology: a transdisciplinary approach INCT-NANOFARMA, which is supported by São Paulo Research Foundation (FAPESP, Brazil) Grant #2014/50928–2 and by “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq, Brazil) Grant # 465687/2014–8. Authors thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brasil); CAPES, Brasil; Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Brasil); and PRPGP-UFSM (PROAP) for their fellowships and financial support.

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Authors and Affiliations

  1. Programa de Pós-Graduação Em Farmacologia, Universidade Federal de Santa Maria (UFSM), Av. Roraima 1000, Santa Maria, RS, Brazil

    Laura Hautrive Milanesi, Jéssica Leandra Oliveira Rosa, Lívia Ferraz D’avila, Vinícia Garzella Metz & Marilise E. Burger

  2. Departamento de Fisiologia E Farmacologia, UFSM, Santa Maria, RS, 97105-900, Brazil

    Domenika Rubert Rossato & Marilise E. Burger

  3. Programa de Pós-Graduação Em Ciências Farmacêuticas, Universidade Federal de Santa Maria (UFSM), Av, Roraima 1000, Santa Maria, RS, Brazil

    Camila Reck Rampelotto & Cristiane de Bona da Silva

  4. Departamento de Farmácia, UFSM, Av Roraima 1000, Santa Maria, RS, Brazil

    Viviane Gonçalves Pereira & Scheila Rezende Schaffazick

  5. Graduation Program of Pharmacology, Physiology and Pharmacology Department, Universidade Federal de Santa Maria (UFSM), Av. Roraima 1000, 97105-900, Santa Maria, RS, Brazil

    Marilise E. Burger

Authors
  1. Laura Hautrive Milanesi
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  2. Domenika Rubert Rossato
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  3. Jéssica Leandra Oliveira Rosa
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  4. Lívia Ferraz D’avila
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  5. Vinícia Garzella Metz
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  6. Camila Reck Rampelotto
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  7. Viviane Gonçalves Pereira
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  9. Cristiane de Bona da Silva
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  10. Marilise E. Burger
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Contributions

The authors Laura Hautrive Milanesi, Domenika Rubert Rossato, Jéssica Leandra Oliveira da Rosa, Lívia Ferraz D’avila, and Vinícia Garzella Metz performed the animal experimental activity, data acquisition, data analysis, and interpretation. Camila Reck Rampelotto, Viviane Gonçalves Pereira, Scheila Rezende Schaffazick, and Cristiane de Bona da Silva participated in the production of the nanoformulations used. Laura Hautrive Milanesi, Domenika Rubert Rossato, and Marilise Escobar Burger worked on the conception and design of the study, writing of the article, critical review of the intellectual content, and final approval of the version to be submitted.

Corresponding author

Correspondence to Marilise E. Burger.

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Ethical approval

We declare that the animal experiment was approved by the Animal Ethical Committee (Universidade Federal de Santa Maria—UFSM), which is affiliated to the Council for Control of Animal Experiments (CONCEA), following international norms of care and animal maintenance.

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The authors declare no competing interests.

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Highlights

• Ferulic acid-loaded nanocapsules (FA-Nc) prevents morphine reinstatement

• FA-Nc /nonencapsulated ferulic acid (FA) are antioxidant in dorsal striatum

• FA-Nc reverses morphine-induced dopaminergic marker changes

• FA-Nc increases NRF2 level in ventral striatum (VS)

• FA-Nc/FA reverse higher level of morphine-induced ΔFosB in VS

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Milanesi, L.H., Rossato, D.R., Rosa, J.L.O. et al. Ferulic acid-loaded nanostructure prevents morphine reinstatement: the involvement of dopamine system, NRF2, and ΔFosB in the striatum brain area of rats. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1535–1545 (2023). https://doi.org/10.1007/s00210-023-02420-w

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