Sex-related differences in pain behaviors following three early life stress paradigms

Background: Early life stress (ELS) serves as a risk factor for the development of functional pain disorders such as irritable bowel syndrome (IBS) in adults. Although rodent models have been developed to mimic different forms of ELS experience, the use of predominantly male animals across various rodent strains has led to a paucity of information regarding sex-related differences in the persistent effects of ELS on pain behaviors in adulthood. We hypothesized that the context or nature of ELS experience may interact with sex differences to influence the development of chronic pain. Methods: We employed three rodent models mimicking different facets of early life adversity to investigate the effects of ELS on pain perception in adulthood. To eliminate strain differences, all experiments were carried out using Long Evans rats. As neonates, male and female rat pups were exposed to maternal separation (MS), limited nesting (LN), or odor attachment learning (OAL). In adulthood, visceral sensitivity and somatic sensitivity were assessed at similar to postnatal day 90 via quantification of visceromotor responses to colorectal distension and von Frey probing, respectively. Results: Following exposure to MS or LN, male rats developed visceral and somatic hypersensitivity compared to controls, whereas females subjected to the same paradigms were normosensitive. In the OAL model, females exposed to unpredictable ELS exhibited visceral but not somatic hypersensitivity. There were no observed differences in visceral or somatic sensitivity in male animals following OAL exposure. Conclusions: In summary, our data confirms that early adverse experiences in the form of MS, LN, and OAL contribute to the long-term development of heightened pain responsiveness in adulthood. Furthermore, this study indicates that sex-related vulnerability or resilience for the development of heightened pain perception is directly associated with the context or nature of the ELS experienced.