Background: The molecular mechanisms underlying itch are constantly being studied to create new opportunities to prevent or alleviate itch. The aim of our study was to determine the spinal gene expression changes induced by compound 48/80 in a mouse itch model. Methods: Mice were divided into saline group (control group, n=12) and compound 48/80 group (48/80 group, n=12). 100 µl saline or compound 48/80 was microinjected intradermally in the nape of the neck. After injection, pruritic behavior was immediately measured every 5 minutes. 30 minutes after injection, tissue was prepared to carry out mRNA profiling microarray and reverse transcription polymerase chain reaction (RT-qPCR) analyses. Results: The total numbers of scratching bout after compound 48/80 injection (100 µg/100 µl) were significantly increased in 48/80 group (190 ± 11.33) as compared with control group (6.83 ± 1.17). We screened the dorsal part of the cervical spinal cord of the mouse itch model for differentially expressed genes. Out of 45037 studied transcripts, the abundance levels of 15 transcripts were altered following compound 48/80 injection. 9 and 6 genes were up-and down-regulated in 48/80 group, respectively. We validated the reliability of the microarray results by RT-qPCR, and found 6 up-regulated mRNA, including Sgk1, Bag4, Fos, Ehd2, Edn3 and Wdfy, were significantly increased, whereas 3 down-regulated mRNA, including Corin, 4921511E18Rik and 4930423020Rik, were significantly decreased. Conclusions: These findings indicate that the alterations of spinal gene expression are involved in acute itch, and provide a translational bridge for spinal drugs targeting their signaling pathway to prevent or alleviate itch.