Dawn K. Prusator

Gender specific effects of neonatal limited nesting on viscerosomatic sensitivity and anxiety‐like behavior in adult rats

Evidence exists to suggest that early life stress (ELS), such as neglect or abuse has profound effects on the developing brain. The current study tests the hypothesis that ELS in the form of neonatal limited nesting (LN) may serve as a predisposing factor for the development of altered nociceptive processing and comorbid increases in anxiety‐like behavior in adulthood.

Animal models of gastrointestinal and liver diseases. Animal models of visceral pain: pathophysiology, translational relevance, and challenges.

Visceral pain describes pain emanating from the thoracic, pelvic, or abdominal organs. In contrast to somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. Animal models have played a pivotal role in our understanding of the mechanisms underlying the pathophysiology of visceral pain. This review focuses on animal models of visceral pain and their translational relevance. In addition, the challenges of using animal models to develop novel therapeutic approaches to treat visceral pain will be discussed.

Sex differences in stress-induced visceral hypersensitivity following early life adversity: a two hit model.

Early life adversity (ELA) has been indicated as a risk factor for the development of stress axis dysfunction in adulthood, specifically in females. We previously showed that unpredictable ELA induces visceral hyperalgesia in adult female rats. It remains to be determined whether ELA alters visceral nociceptive responses to stress in adulthood. The current study tested the hypothesis that following ELA, exposure to an adulthood stressor, or second hit, serves as a risk factor for exaggerated stress‐induced visceral hypersensitivity that is sex‐specific.

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

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.

Neurobiology of early life stress and visceral pain: translational relevance from animal models to patient care.

Epidemiological studies show that females are twice as likely to receive a diagnosis of irritable bowel syndrome (IBS) than their male counterparts. Despite evidence pointing to a role for sex hormones in the onset or exacerbation of IBS symptoms, the mechanism by which ovarian hormones may predispose women to develop IBS remains largely undefined. On the other hand, there is a growing body of research showing a correlation between reports of early life stress (ELS) and the diagnosis of IBS. Current treatments available for IBS patients target symptom relief including abdominal pain and alterations in bowel habits, but are not directed to the etiology of the disease.

Sexually dimorphic effects of early life stress in rat pups on urinary bladder detrusor muscle contractility in adulthood

BackgroundPainful bladder syndrome/interstitial cystitis (PBS/IC) is a chronic disorder that is commonly seen in women who report a history of adversity in early life. Here, we test the hypothesis that early life stress (ELS) induces sexually dimorphic abnormalities in urinary bladder smooth muscle function in adulthood.MethodsMale and female rat pups were conditioned on postnatal (PN) days 8–12 with either a “predictable or “unpredictable” odor-shock, or odor only control treatment. In adulthood, urinary bladder function was assessed in vivo via urine spot analysis and in vitro via contractile responses to electrical field stimulation (EFS) and membrane depolarization with potassium chloride (KCl).ResultsIn adulthood, we found that female rats exposed to unpredictable ELS showed a significant (p < 0.05) increase in urine voiding volume compared to predictable ELS or controls. We also found that detrusor muscle contractile responses to EFS were significantly (p < 0.001) decreased following unpredictable ELS in adult female rats compared to the predictable ELS or controls. In male rats exposed to ELS, there was no difference in voiding volume or EFS-induced contractility between groups. In adulthood, the myogenic smooth muscle response to KCl was not significantly different between groups. Histological analysis from adult female and male rats revealed no differences in the appearance of the urinary bladder in rats exposed to ELS.ConclusionsIn summary, our findings provide evidence to support abnormalities in the nerve-mediated contractile responses of the detrusor smooth muscle in adult female rats following ELS. We speculate that these sexually dimorphic alterations in urinary bladder function may account, at least in part, for the female predominance of PBS/IC.

Sex-Related Differences in GI Disorders

Epidemiological studies indicate sex-related differences among functional gastrointestinal disorders (FGIDs) wherein females are more likely to receive a diagnosis than their male counterparts. However, the mechanism by which females exhibit an increased vulnerability for development of these pathophysiologies remains largely unknown, and therapeutic treatments are limited. The current chapter focuses on clinical research outlining our current knowledge of factors that contribute to the female predominance among FGID patients such as the menstrual cycle and sex hormones. In addition, we will discuss progress in preclinical research, including animal models, which serve as valuable tools for the investigation of the development and long term manifestation of symptoms observed within the patient population. Although much progress has been made, additional longitudinal studies in both clinical and preclinical research are necessary to identify more specific mechanisms underlying sex-related differences in FGIDs as well as targets for improved therapeutic approaches.

Psychological stress‐induced colonic barrier dysfunction: Role of immune‐mediated mechanisms

Evidence suggests that patients with irritable bowel syndrome (IBS) exhibit increases in gut permeability and alterations in tight junction (TJ) protein expression. Although psychological stress worsens IBS symptoms, the mechanisms by which stress enhances gut permeability and affects TJ protein expression remain to be determined. Here, we test the hypothesis that chronic intermittent psychological stress activates the release of proinflammatory cytokines to alter TJ proteins and promotes increased gut permeability.

Epigenetics of Pain Management

Abstract Although currently available therapeutics provide moderate relief from acute pain, therapeutic agents used for treating chronic pain are typically limited by adverse side effects, including tolerance, addiction, and constipation. Thus, there is a significant medical need for novel therapies devoid of serious adverse effects for the treatment of chronic pain. Histone deacetylase inhibitors and other epigenetic drugs, such as histone acetlytransferases inhibitors, have been shown to have a role in managing pain perception. This chapter will briefly review spinal and central pain pathways mediating nociception. We will discuss the animal models, which have enhanced our understanding of how epigenetic processes may play a role in the pathophysiological mechanisms of chronic pain. We will also review the basic molecular epigenetic mechanisms of pain processing, and throughout the chapter the authors have attempted to critically evaluate the latest research from both experimental animal models and human studies to highlight the role of epigenetic drugs in managing both acute and chronic pain. However, it is pertinent to note that the role of epigenetics in pain perception is a field in its infancy, and thus limited data is to hand of the exact molecular mechanisms that mediate pain perception.

Stereotaxic Exposure of the Central Nucleus of the Amygdala to Corticosterone Increases Colonic Permeability and Reduces Nerve-Mediated Active Ion Transport in Rats

Background: Irritable bowel syndrome (IBS) is characterized by visceral pain and abnormal bowel habits that are worsened during stress. Evidence also suggests altered intestinal barrier function in IBS. Previously, we demonstrated that stereotaxic application of the stress hormone corticosterone (CORT) onto the central nucleus of the amygdala (CeA) induces colonic hyperalgesia and anxiety-like behavior in a rat model, however the effect on intestinal permeability and mucosal function remain to be evaluated. Methods: Male Fischer 344 rats underwent bilateral stereotaxic implantation of CORT or inert cholesterol (CHOL)-containing micropellets (30 μg) onto the dorsal margin of the CeA. Seven days later, colonic tissue was isolated to assess tissue permeability in modified Ussing chambers via transepithelial electrical resistance (TEER) and macromolecular flux of horseradish peroxidase (HRP). Secretory responses to electrical field stimulation (EFS) of submucosal enteric nerves as well as activation with forskolin were used to assess movements of ions across the isolated colonic tissues. In a separate cohort, colonic histology, and mast cell infiltration was assessed. Key Results: Compared to CHOL-implanted controls, we determined that exposing the CeA to elevated levels of CORT significantly increased macromolecular flux across the colonic epithelial layer without changing TEER. Nerve-mediated but not cAMP-mediated active transport was inhibited in response to elevated amygdala CORT. There were no histological changes or increases in mast cell infiltration within colonic tissue from CORT treated animals. Conclusion and Inferences: These observations support a novel role for the CeA as a modulator of nerve-mediated colonic epithelial function.