Fig. 1: PRISMA diagram.

The review protocol was registered prospectively in Prospero (record ID#CRD42022270113), and followed the Preferred Reporting Items for Systematic Review and Meta-Analysis protocol (PRISMA [187]). Identification of studies. Three databases were used for systematic screening: MEDLINE, Embase and Web of Science. The literature search was performed using the following keywords: “microarray” OR “RNA sequencing” OR “bisulfite sequencing” OR “chromatin immunopurification sequencing” OR “single cell RNA sequencing” AND each of the following terms: “opiates”, “opioid”, “morphine”, “fentanyl”, “oxycodone”, “heroin”, “methadone” or “buprenorphine”. The initial search provided 2709 potentially eligible studies. Screening. Articles were screened based on their title and abstract, and included if they used a high-throughput, genome-wide methodology to assess modifications of gene expression or epigenetic mechanisms as a function of opioid exposure, in the nervous system of primates or rodents (rat, mouse), and were published in English in peer-reviewed journals. Exclusion criteria included tissue other than the nervous system and candidate gene approaches. Once duplicates were removed, a total of 1229 articles were screened, among which 1067 were excluded because their title or abstract didn’t meet eligibility criteria. Eligibility. After a more thorough examination of articles’ full-text, an additional 89 articles were excluded. As a result, 73 papers were selected for qualitative synthesis. Among these, 44 articles reporting on transcriptomic analyses in the 5 most frequently investigated regions were selected for a more detailed quantitative synthesis. Of these, 34 articles investigated a single brain region, 9 covered 2 regions, and only 1 characterized 5 regions [13]. Overall, this resulted in 52 differential expression analyses: 18, 11, 11, 6 and 6 in the nucleus accumbens (NAc), frontal cortex, whole striatum, dorsal striatum and spinal cord, respectively.