Oxycodone is one a commonly used medication for
pain, and is also a widely abused prescription
opioid, like other short-acting MOPr agonists. Neurochemical and structural adaptations in brain following chronic MOPr-agonist administration are thought to underlie pathogenesis and persistence of
opiate addiction. Many axon guidance molecules, such as
integrins,
semaphorins, and
ephrins may contribute to
oxycodone-induced neuroadaptations through alterations in axon-target connections and synaptogenesis, that may be implicated in the behaviors associated with
opiate addiction. However, little is known about this important area. The aim of this study is to investigate alterations in expression of selected
integrin,
semaphorin,
ephrins,
netrin, and slit genes in the nucleus accumbens (NAc) and caudate putamen (CPu) of mice following extended 14-day
oxycodone self-administration (SA), using RNAseq. Methods: Total
RNA from the NAc and CPu were isolated from adult male C57BL/6J mice within 1 h after the last session of
oxycodone in a 14-day
self-administration paradigm (4h/day, 0.25 mg/kg/infusion, FR1) or from yoked saline controls. Gene expressions were examined using
RNA sequencing (
RNA-Seq) technology.
RNA-Seq libraries were prepared using Illumina's TruSeq® Stranded Total
RNA LT kit. The reads were aligned to the mouse reference genome (version mm10) using STAR. DESeq2 was applied to the counts of
protein coding genes to estimate the fold change between the treatment groups. False Discovery Rate (FDR) q < 0.1 were used to select genes that have a significant expression change. For selection of a subset of genes related to axon guidance pathway, REACTOME was used. Results: Among 38 known genes of the
integrin,
semaphorin, and
ephrin gene families,
RNA-seq data revealed up-regulation of six genes in the NAc: heterodimer receptor,
integrins Itgal, Itgb2, and Itgam, and its
ligand semaphorin Sema7a, two
semaphorin receptors, plexins Plxnd1 and Plxdc1. There was down-regulation of eight genes in this region: two
integrin genes Itga3 and Itgb8,
semaphorins Sema3c, Sema4g, Sema6a, Sema6d,
semaphorin receptor
neuropilin Nrp2, and
ephrin receptor Epha3. In the CPu, there were five differentially expressed axon guidance genes: up-regulation of three
integrin genes, Itgal, Itgb2, Itga1, and down-regulation of Itga9 and
ephrin Efna3 were thus observed. No significant alterations in expression of
Netrin-1 or Slit were observed. Conclusion: We provide evidence for alterations in the expression of selective axon guidance genes in adult mouse brain following chronic
self-administration of
oxycodone. Further examination of
oxycodone-induced changes in the expression of these specific axon guidance molecules and
integrin genes in relation to behavior may provide new insights into development of addiction to
oxycodone.