Sex Differences in Visceral Pain and Comorbidities: Clinical Outcomes, Preclinical Models, and Cellular and Molecular Mechanisms

Abstract

Sexual dimorphism of visceral pain has been documented in clinics and experimental animal models. Aside from hormones, emerging evidence suggests the sex-differential intrinsic neural regulation of pain generation and maintenance. According to the International Association for the Study of Pain (IASP) and the American College of Gastroenterology (ACG), up to 25% of the population have visceral pain at any one time, and in the United States 10-15 percent of adults suffer from irritable bowel syndrome (IBS). Here we examine the preclinical and clinical evidence of sex differences in visceral pain focusing on IBS, other forms of bowel dysfunction and IBS-associated comorbidities. We summarize preclinical animal models that provide a means to investigate the underlying molecular mechanisms in the sexual dimorphism of visceral pain. Neurons and nonneuronal cells (glia and immune cells) in the peripheral and central nervous systems, and the communication of gut microbiota and neural systems all contribute to sex-dependent nociception and nociplasticity in visceral painful signal processing. Emotion is another factor in pain perception and appears to have sexual dimorphism.

Keywords: clinical; molecule; pain; preclinical; sex; visceral.

Figure 1

Visceral pain emanates from or is associated with inflammation, injury, gut microbiota imbalance, stress, psychiatric disorders, and somatic pain. Neuroplasticity in the peripheral and central nervous systems, including changes in the properties of neurons, glial cells and immune cells, plays a role in visceral pain and associated comorbidities.

Figure 2

Comparison of hind paw mechanical sensitivity in male (a) and female (b) mice after TNBS-induced colitis. Male: control n = 6, colitis n = 7; female day 4: control n = 5; colitis n = 10; female day 7 and 21: control n = 7, colitis n = 7. Two-way ANOVA with Tukey’s multiple comparison test. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.