Repeated morphine exposure activates synaptogenesis and other neuroplasticity-related gene networks in the dorsomedial prefrontal cortex of male and female rats

Shirelle X. Liu, Mari S. Gades, Yayi Swain, Aarthi Ramakrishnan, Andrew C. Harris, Phu V. Tran, Jonathan C. Gewirtz

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Opioid abuse is a chronic disorder likely involving stable neuroplastic modifications. While a number of molecules contributing to these changes have been identified, the broader spectrum of genes and gene networks that are affected by repeated opioid administration remain understudied. Methods: We employed Next-Generation RNA-sequencing (RNA-seq) followed by quantitative chromatin immunoprecipitation to investigate changes in gene expression and their regulation in adult male and female rats’ dorsomedial prefrontal cortex (dmPFC) after a regimen of daily injection of morphine (5.0 mg/kg; 10 days). Ingenuity Pathway Analysis (IPA) was used to analyze affected molecular pathways, gene networks, and associated regulatory factors. A complementary behavioral study evaluated the effects of the same morphine injection regimen on locomotor activity, pain sensitivity, and somatic withdrawal signs. Results: Behaviorally, repeated morphine injection induced locomotor hyperactivity and hyperalgesia in both sexes. 90 % of differentially expressed genes (DEGs) in morphine-treated rats were upregulated in both males and females, with a 35 % overlap between sexes. A substantial number of DEGs play roles in synaptic signaling and neuroplasticity. Chromatin immunoprecipitation revealed enrichment of H3 acetylation, a transcriptionally activating chromatin mark. Although broadly similar, some differences were revealed in the gene ontology networks enriched in females and males. Conclusions: Our results cohere with findings from previous studies based on a priori gene selection. Our results also reveal novel genes and molecular pathways that are upregulated by repeated morphine exposure, with some common to males and females and others that are sex-specific.

Original languageEnglish (US)
Article number108598
JournalDrug and alcohol dependence
Volume221
DOIs
StatePublished - Apr 1 2021

Bibliographical note

Funding Information:
This work was supported by R21 DA037728, U01 DA051993 and T32 DA007097, and by grants from the Engdahl Family Research Fund and the Office of the Vice President for Research, University of Minnesota, and the Hennepin Healthcare Research Institute Career Development Award.

Funding Information:
This work was supported by R21 DA037728 , U01 DA051993 and T32 DA007097 , and by grants from the Engdahl Family Research Fund and the Office of the Vice President for Research , University of Minnesota , and the Hennepin Healthcare Research Institute Career Development Award .

Publisher Copyright:
© 2021 Elsevier B.V.

Keywords

  • Addiction
  • Opioid
  • Plasticity
  • Prefrontal cortex
  • RNA-sequencing

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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