Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Oct 7

PMID 34616393

Citations 2

Authors

Javier Cuitavi

Jesus David Lorente

Yolanda Campos-Jurado

Ana Polache

Lucia Hipolito

Affiliations

Soon will be listed here.

Abstract

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1β also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1β, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1β, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.

Citing Articles

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Sex-dependent factors of alcohol and neuroimmune mechanisms.

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References

Hoogland I, Houbolt C, van Westerloo D, van Gool W, van de Beek D . Systemic inflammation and microglial activation: systematic review of animal experiments. J Neuroinflammation. 2015; 12:114. PMC: 4470063. DOI: 10.1186/s12974-015-0332-6. View

Gessi S, Borea P, Bencivenni S, Fazzi D, Varani K, Merighi S . The activation of μ-opioid receptor potentiates LPS-induced NF-kB promoting an inflammatory phenotype in microglia. FEBS Lett. 2016; 590(17):2813-26. DOI: 10.1002/1873-3468.12313. View

Mitchell J, ONeil J, Janabi M, Marks S, Jagust W, Fields H . Alcohol consumption induces endogenous opioid release in the human orbitofrontal cortex and nucleus accumbens. Sci Transl Med. 2012; 4(116):116ra6. DOI: 10.1126/scitranslmed.3002902. View

Bradley T, Peppa D, Pedroza-Pacheco I, Li D, Cain D, Henao R . RAB11FIP5 Expression and Altered Natural Killer Cell Function Are Associated with Induction of HIV Broadly Neutralizing Antibody Responses. Cell. 2018; 175(2):387-399.e17. PMC: 6176872. DOI: 10.1016/j.cell.2018.08.064. View

Agustin-Pavon C, Mielcarek M, Garriga-Canut M, Isalan M . Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice. Mol Neurodegener. 2016; 11(1):64. PMC: 5013590. DOI: 10.1186/s13024-016-0128-x. View

Siemsen B, Landin J, McFaddin J, Hooker K, Chandler L, Scofield M . Chronic intermittent ethanol and lipopolysaccharide exposure differentially alter Iba1-derived microglia morphology in the prelimbic cortex and nucleus accumbens core of male Long-Evans rats. J Neurosci Res. 2020; 99(8):1922-1939. PMC: 7779701. DOI: 10.1002/jnr.24683. View

Campos-Jurado Y, Lorente J, Gonzalez-Romero J, Granero L, Polache A, Hipolito L . Impaired alcohol-induced dopamine release in the nucleus accumbens in an inflammatory pain model: behavioral implications in male rats. Pain. 2020; 161(9):2203-2211. DOI: 10.1097/j.pain.0000000000001915. View

Gilpin N, Koob G . Neurobiology of alcohol dependence: focus on motivational mechanisms. Alcohol Res Health. 2009; 31(3):185-95. PMC: 2770186. View

Azuma Y, Ohura K . Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells. Scand J Immunol. 2002; 56(3):260-9. DOI: 10.1046/j.1365-3083.2002.01128.x. View

10.

Parent A, Beaudet N, Beaudry H, Bergeron J, Berube P, Drolet G . Increased anxiety-like behaviors in rats experiencing chronic inflammatory pain. Behav Brain Res. 2012; 229(1):160-7. PMC: 3848972. DOI: 10.1016/j.bbr.2012.01.001. View

11.

Yang B, Deng G, Zhao R, Dai C, Jiang C, Wang X . Porous Se@SiO nanosphere-coated catheter accelerates prostatic urethra wound healing by modulating macrophage polarization through reactive oxygen species-NF-κB pathway inhibition. Acta Biomater. 2019; 88:392-405. DOI: 10.1016/j.actbio.2019.02.006. View

12.

Lupp A, Richter N, Doll C, Nagel F, Schulz S . UMB-3, a novel rabbit monoclonal antibody, for assessing μ-opioid receptor expression in mouse, rat and human formalin-fixed and paraffin-embedded tissues. Regul Pept. 2010; 167(1):9-13. DOI: 10.1016/j.regpep.2010.09.004. View

13.

Sanchez-Catalan M, Hipolito L, Guerri C, Granero L, Polache A . Distribution and differential induction of CYP2E1 by ethanol and acetone in the mesocorticolimbic system of rat. Alcohol Alcohol. 2008; 43(4):401-7. DOI: 10.1093/alcalc/agn012. View

14.

Tan Y, Yuan Y, Tian L . Microglial regional heterogeneity and its role in the brain. Mol Psychiatry. 2019; 25(2):351-367. PMC: 6974435. DOI: 10.1038/s41380-019-0609-8. View

15.

He J, Crews F . Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol. 2008; 210(2):349-58. PMC: 2346541. DOI: 10.1016/j.expneurol.2007.11.017. View

16.

Klawonn A, Fritz M, Castany S, Pignatelli M, Canal C, Simila F . Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons. Immunity. 2021; 54(2):225-234.e6. DOI: 10.1016/j.immuni.2020.12.016. View

17.

Lorente J, Cuitavi J, Campos-Jurado Y, Monton-Molina R, Gonzalez-Romero J, Hipolito L . Kappa opioid receptor blockade in the nucleus accumbens shell prevents sex-dependent alcohol deprivation effect induced by inflammatory pain. Pain. 2021; 163(1):e137-e147. DOI: 10.1097/j.pain.0000000000002332. View

18.

Barton E, Baker C, Leasure J . Investigation of Sex Differences in the Microglial Response to Binge Ethanol and Exercise. Brain Sci. 2017; 7(10). PMC: 5664066. DOI: 10.3390/brainsci7100139. View

19.

Zhao Y, Tian X, Liu G, Wang K, Xie Y, Qiu Y . Berberine protects myocardial cells against anoxia-reoxygenation injury via p38 MAPK-mediated NF-κB signaling pathways. Exp Ther Med. 2019; 17(1):230-236. PMC: 6307361. DOI: 10.3892/etm.2018.6949. View

20.

Borner C, Kraus J, Schroder H, Ammer H, Hollt V . Transcriptional regulation of the human mu-opioid receptor gene by interleukin-6. Mol Pharmacol. 2004; 66(6):1719-26. DOI: 10.1124/mol.104.003806. View