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

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.

BXD recombinant inbred strains participate in social preference, anxiety and depression behaviors along sex-differences in cytokines and tactile allodynia

“…Explaining the observed sex-differences is challenging despite the consistency with others studies. For example, male rats developed visceral and somatic hypersensitivity compared to controls following exposure to maternal separation and limited nesting, whereas females subjected to the same paradigms were normosensitive (Prusator and Meerveld, 2016). The difference in allodynia conditions between males and females might be attributed to sex hormones (Mogil, 2012; Woller et al, 2015).…”

“…The difference in allodynia conditions between males and females might be attributed to sex hormones (Mogil, 2012; Woller et al, 2015). Female hormones may increase the sensitivity for developing chronic pain or decrease the nociception of pain, dependent upon the menses cycle (Prusator and Meerveld, 2016). In addition, it appears that the female brain might be more resistant to the inflammatory process than the male brain via Nrf2 upregulation by sex steroid hormones, such as 17β-estradiol (Zhu et al, 2015).…”

Mechanisms of Stress-induced Visceral Pain

“…118 Furthermore, in adulthood, these models of ELS have been shown to induce chronic, sexually dimorphic visceral hypersensitivity. 119 As a model for neglect, maternal separation induces visceral hyperalgesia and enhanced HPA-activity in adulthood compared to non-separated controls. Visceral hypersensitivity has also been observed in adult rats following ELS induced by limited nesting, a model for poverty-associated neglect or abuse.…”

“…Loss of promoter region acetylation lead to decreased GR expression within the CeA and a subsequent increase in the expression of CRH due to a loss of GR-mediated repression. 119 Bilateral CeA-infusions of TSA or SAHA inhibited visceral hypersensitivity by preventing the change in histone acetylation. 62 Concurrently, another laboratory employed the water avoidance stress model to investigate epigenetic mechanisms of visceral hypersensitivity within the dorsal root ganglion (DRG).…”

Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics

“…In these models, rats exposed to prenatal or neonatal stress exhibit visceral hypersensitivity in adulthood . Animal models of maternal separation, limited nesting, and odor‐associated learning demonstrate visceral hypersensitivity in adulthood, long after the initial stressor in neonatal life has been removed . Compared to undisturbed littermates, animals that received neonatal stress had long‐lasting changes in gene expression, underlying and inducing visceral hypersensitivity.…”