Abstract
BackgroundEarly 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.MethodsWe 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 ~postnatal day 90 via quantification of visceromotor responses to colorectal distension and von Frey probing, respectively.ResultsFollowing 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.ConclusionsIn 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.
Highlights
Life stress (ELS) serves as a risk factor for the development of functional pain disorders such as irritable bowel syndrome (IBS) in adults
We present parallel assessments of the maternal separation (MS), limited nesting (LN), and odor attachment learning (OAL) models of Early life stress (ELS) using male and female Long Evans rats to address that hypothesis that the development of chronic pain in adulthood is influenced by sex differences in either the vulnerability or resilience to a specific ELS experience
Post hoc analysis revealed that adult males previously exposed to MS showed a decreased threshold for hindpaw withdrawal compared to controls (p < 0.0001) (Fig. 2a), whereas females exposed to MS exhibited no somatic allodynia as adults (p > 0.05) (Fig. 2b)
Summary
Life stress (ELS) serves as a risk factor for the development of functional pain disorders such as irritable bowel syndrome (IBS) in adults. Validated models of ELS include (1) maternal separation (MS) developed to model neglect and abuse, (2) limited nesting (LN) developed to model abuse as a result of an impoverished environment, and (3) odor attachment learning (OAL) which models attachment to an abusive caregiver These ELS models have been shown to induce heightened visceral pain in addition to changes in gut permeability, anxiety-like behaviors, and adult responses to stress [10,11,12,13,14]. Inconsistent use of male and female animals and rodent strains limits our ability to fully compare the long-term effects of ELS on pain across studies. The current study fills an important gap by performing a comprehensive and comparative analysis of several ELS models using male and female animals from a single rodent strain to investigate visceral and somatic pain thresholds in adulthood
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