〔Abstract〕 Objective To investigate the regulatory effect and mechanism of specific antagonist of acid-sensitive ion channel 3(APETx2) on visceral sensitivity in mice with post-infectious irritable bowel syndrome(PI-IBS). Methods The PI-IBS model was established by National Institutes of Health(NIH) mice infected with Trichinella spiralis. Gastrointestinal transport function was assessed by measuring the time to first black stool and the number of fecal pellets collected for 6 hours; abdominal wall withdrawal reflex(AWR) was used to assess visceral sensitivity; the expression of calcitonin gene-related peptide(CGRP) in the colon tissue was detected by immunohistochemistry; the expression of brain-derived neurotrophic factor(BDNF) and CGRP mRNA in the colon tissues was detected by quantitative real time polymerase chain reaction(qRT-PCR). The expression levels of acid sensing ion channel 3(ASIC3), CGRP, and transient receptor potential vanilloid 1(TRPV1) protein in brain tissue were detected by Western blot analysis. Results Compared with the control group, the PI-IBS group significantly reduced the time of first black stool, the number of fecal particles and AWR score within 6 hours significantly increased, the protein expression of CGRP in colon tissue, BDNF and CGRP mRNA significantly increased, and the protein expression of CGRP, ASIC3 and TRPV1 in brain tissue significantly increased. Compared with the control group, the PI-IBS group significantly reduced the time to first black stool, the number of fecal particles and AWR score within 6 hours significantly increased, the expression of CGRP protein in colon tissue, the expression of BDNF and CGRP mRNA significantly increased, and the protein expression of CGRP, ASIC3 and TRPV1 in brain tissue significantly increased; compared with the PI-IBS group, the first time of black stool clearance in the APETx2 group was significantly prolonged, the number of fecal particles and AWR score within 6 hours were significantly reduced, the expression of CGRP protein in colon tissue, the expression of BDNF and CGRP mRNA was significantly reduced, the protein expression of CGRP, ASIC3 and TRPV1 in brain tissue was significantly reduced, and the difference was statistically significant(P<0.05). Conclusion APETx2 can alleviate visceral sensitivity and regulate gastrointestinal motility in PI-IBS mice by downregulating the expression of BDNF, CGRP, ASIC3 and TRPV1. APETx2 may provide a new therapeutic option for the treatment of IBS.