Sex differences in pain-related behaviors and clinical progression of disease in mouse models of colonic pain

Abstract

Previous studies have reported sex differences in patients with irritable bowel syndrome and inflammatory bowel disease, including differences in visceral pain perception. Despite this, sex differences in behavioral manifestations of visceral pain and underlying pathology of the gastrointestinal tract have been largely understudied in preclinical research. In this study, we evaluated potential sex differences in spontaneous nociceptive responses, referred abdominal hypersensitivity, disease progression, and bowel pathology in mouse models of acute and persistent colon inflammation. Our experiments show that females exhibit more nociceptive responses and referred abdominal hypersensitivity than males in the context of acute but not persistent colon inflammation. We further demonstrate that, after acute and persistent colon inflammation, pain-related behavioral responses in females and males are distinct, with increases in licking of the abdomen only observed in females and increases in abdominal contractions only seen in males. During persistent colon inflammation, males exhibit worse disease progression than females, which is manifested as worse physical appearance and higher weight loss. However, no measurable sex differences were observed in persistent inflammation-induced bowel pathology, stool consistency, or fecal blood. Overall, our findings demonstrate sex differences in pain-related behaviors and disease progression in the context of acute and persistent colon inflammation, highlighting the importance of considering sex as a biological variable in future mechanistic studies of visceral pain as well as in the development of diagnostics and therapeutic options for chronic gastrointestinal diseases.