Identification of Arginine-Vasopressin Receptor 1a (Avpr1a/Avpr1a) as a Novel Candidate Gene for Chronic Visceral Pain Sheds Light on the Potential Role of Enteric Neurons in the Development of Visceral Hypersensitivity.

Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While the etiology of DGBIs remains poorly understood, there is evidence that both genetic and environmental factors play a role. In this study, we report the identification and validation of arginine-vasopressin receptor 1A (Avpr1a) as a novel candidate gene for visceral hypersensitivity (VH), a primary peripheral mechanism underlying abdominal pain in DGBI/IBS.

Identification of arginine-vasopressin receptor 1a (Avpr1a/AVPR1A) as a novel candidate gene for chronic visceral pain.

Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While the etiology of DGBIs remains poorly understood, there is evidence that both genetic and environmental factors play a role. In this study, we report the identification and validation of as a novel candidate gene for visceral hypersensitivity (VH), a primary peripheral mechanism underlying abdominal pain in DGBI/IBS.

Exposure to early-life stress impairs weight-loss maintenance success in mice.

Objective: The impact of early-life stress on weight-loss maintenance is unknown.

Methods: Mice underwent neonatal maternal separation (NMS) from 0 to 3 weeks and were weaned onto a high-fat sucrose diet (HFSD) from 3 to 20 weeks. Calorie-restricted weight loss on a low-fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks.

Exposure to early life stress impairs weight loss maintenance success in mice.

Early life stress increases obesity risk, but its impact on weight loss maintenance is unknown. Mice underwent neonatal maternal separation (NMS) from 0-3 weeks and were weaned onto high fat sucrose diet (HFSD) from 3-20 weeks. Calorie-restricted weight loss on a low fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks.

Early-life stress perturbs the epigenetics of Cd36 concurrent with adult onset of NAFLD in mice.

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide.

High-fat/high-sucrose diet worsens metabolic outcomes and widespread hypersensitivity following early-life stress exposure in female mice.

Exposure to stress early in life has been associated with adult-onset comorbidities such as chronic pain, metabolic dysregulation, obesity, and inactivity. We have established an early-life stress model using neonatal maternal separation (NMS) in mice, which displays evidence of increased body weight and adiposity, widespread mechanical allodynia, and hypothalamic-pituitary-adrenal axis dysregulation in male mice. Early-life stress and consumption of a Western-style diet contribute to the development of obesity; however, relatively few preclinical studies have been performed in female rodents, which are known to be protected against diet-induced obesity and metabolic dysfunction.

Reduced Hippocampal Volume and Neurochemical Response to Adult Stress Exposure in a Female Mouse Model of Urogenital Hypersensitivity.

Early life stress exposure significantly increases the risk of developing chronic pain syndromes and comorbid mood and metabolic disorders later in life. Structural and functional changes within the hippocampus have been shown to contribute to many early life stress-related outcomes. We have previously reported that adult mice that underwent neonatal maternal separation (NMS) exhibit urogenital hypersensitivity, altered anxiety- and depression-like behaviors, increased adiposity, and decreased gene expression and neurogenesis in the hippocampus.

Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-Induced Weight Gain in Male Mice.

The central integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previously, increased acute food intake following the chemical reduction of hepatic fatty acid oxidation and ATP levels was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism.

Voluntary Wheel Running Partially Attenuates Early Life Stress-Induced Neuroimmune Measures in the Dura and Evoked Migraine-Like Behaviors in Female Mice.

Migraine is a complex neurological disorder that affects three times more women than men and can be triggered by endogenous and exogenous factors. Stress is a common migraine trigger and exposure to early life stress increases the likelihood of developing chronic pain disorders later in life. Here, we used our neonatal maternal separation (NMS) model of early life stress to investigate whether female NMS mice have an increased susceptibility to evoked migraine-like behaviors and the potential therapeutic effect of voluntary wheel running.

An Omega-3-rich Anti-inflammatory Diet Improved Widespread Allodynia and Worsened Metabolic Outcomes in Adult Mice Exposed to Neonatal Maternal Separation.

Inflammation plays a key role in the progression and maintenance of chronic pain, which impacts the lives of millions of Americans. Despite growing evidence that chronic pain can be improved by treating underlying inflammation, successful treatments are lacking and pharmaceutical interventions are limited due to drug side effects. Here we are testing whether a 'healthy human' diet (HHD), with or without anti-inflammatory components (HHAID), improves pain-like behaviors in a preclinical model of chronic widespread hypersensitivity induced by neonatal maternal separation (NMS).

The impact of foot shock-induced stress on pain-related behavior associated with burn injury.

Acute pain is prevalent following burn injury and can often transition to chronic pain. Prolonged acute pain is an important risk factor for chronic pain and there is little preclinical research to address this problem. Using a mouse model of second-degree burn, we investigated whether pre-existing stress influences pain(sensitivity) after a burn injury.

Voluntary wheel running improves outcomes in an early life stress-induced model of urologic chronic pelvic pain syndrome in male mice.

Patients with a history of early life stress (ELS) exposure have an increased risk of developing chronic pain and mood disorders later in life. The severity of ELS in patients with urologic chronic pelvic pain syndrome (UCPPS) is directly correlated with symptom severity and increased comorbidity, and is inversely related to likelihood of improvement. Voluntary exercise improves chronic pain symptoms, and our group and others have shown that voluntary wheel running can improve outcomes in stress-induced UCPPS models, suggesting that exercise may negate some of the outcomes associated with ELS.

Difference in Housing Temperature-Induced Energy Expenditure Elicits Sex-Specific Diet-Induced Metabolic Adaptations in Mice.

Objective: The aim of this study was to test whether increased energy expenditure (EE), independent of physical activity, reduces acute diet-induced weight gain through tighter coupling of energy intake to energy demand and enhanced metabolic adaptations.

Methods: Indirect calorimetry and quantitative magnetic resonance imaging were used to assess energy metabolism and body composition during 7-day high-fat/high-sucrose (HFHS) feeding in male and female mice housed at divergent temperatures (20°C vs. 30°C).

Early life stress reduces voluntary exercise and its prevention of diet-induced obesity and metabolic dysfunction in mice.

The development of obesity-related metabolic syndrome (MetS) involves a complex interaction of genetic and environmental factors. One environmental factor found to be significantly associated with MetS is early life stress (ELS). We have previously reported on our mouse model of ELS, induced by neonatal maternal separation (NMS), that displays altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis and increased sensitivity in the urogenital organs, which was attenuated by voluntary wheel running.

Foot shock stress generates persistent widespread hypersensitivity and anhedonic behavior in an anxiety-prone strain of mice.

A significant subset of patients with urologic chronic pelvic pain syndrome suffer from widespread, as well as pelvic, pain and experience mood-related disorders, including anxiety, depression, and panic disorder. Stress is a commonly reported trigger for symptom onset and exacerbation within these patients. The link between stress and pain is believed to arise, in part, from the hypothalamic-pituitary-adrenal axis, which regulates the response to stress and can influence the perception of pain.

Influence of Abuse History on Concurrent Benzodiazepine and Opioid Use in Chronic Pain Patients.

An important predictor of opioid overdose is co-use of benzodiazepines, which are often prescribed for anxiety. Coping with anxiety may be particularly difficult among individuals with a history of abuse, as it is often linked to higher pain severity and poorer coping skills. We explored whether abuse history moderated the association between anxiety and benzodiazepine use among current opioid users.

Potential Mechanisms Underlying Centralized Pain and Emerging Therapeutic Interventions.

Centralized pain syndromes are associated with changes within the central nervous system that amplify peripheral input and/or generate the perception of pain in the absence of a noxious stimulus. Examples of idiopathic functional disorders that are often categorized as centralized pain syndromes include fibromyalgia, chronic pelvic pain syndromes, migraine, and temporomandibular disorder. Patients often suffer from widespread pain, associated with more than one specific syndrome, and report fatigue, mood and sleep disturbances, and poor quality of life.

Voluntary wheel running attenuates urinary bladder hypersensitivity and dysfunction following neonatal maternal separation in female mice.

Aims: Patients with interstitial cystitis/painful bladder syndrome (IC/PBS) commonly suffer from widespread pain and mood disorder, which has been attributed to improper functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Voluntary exercise has been shown to improve HPA axis function, therefore we are determining whether voluntary wheel running can attenuate urological pain and dysfunction following neonatal maternal separation (NMS) in female mice.

Methods: Mice underwent NMS for 3 h/day from postnatal Day 1-21, were caged with free access to running wheels at 4 weeks of age, and assessed 4 weeks later for bladder sensitivity, micturition, reward behavior, mast cell degranulation, and HPA axis-related in vitro analysis.

The Influence of Early Life Experience on Visceral Pain.

Pain is the most reported and troublesome symptom of nearly all functional disorders affecting the genitourinary and gastrointestinal organs. Patients with irritable bowel syndrome (IBS), interstitial cystitis/painful bladder syndrome (IC/PBS), vulvodynia, and/or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS; collectively termed chronic pelvic pain syndromes) report pain severe enough to impact quality of life and often suffer from symptoms of or are diagnosed with more than one of these syndromes. This increased comorbidity between chronic pelvic pain syndromes, and with pain disorders of disparate body regions, as well as with mood disorders, can be influenced by disruptions in the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the response to stress and influences the perception of pain.

Differential Influence of Early Life and Adult Stress on Urogenital Sensitivity and Function in Male Mice.

Experiences of adverse childhood events have been associated with improper output of the hypothalamic-pituitary-adrenal (HPA) axis in adulthood, as well as development of comorbid functional pain disorders. Symptoms of chronic prostatitis/chronic pelvic pain syndrome frequently overlap with those of interstitial cystitis/painful bladder syndrome and symptom severity is often triggered by stress. The objective of this study was to investigate the influence early life stress and acute adult stress on (1) perigenital sensitivity, (2) micturition, (3) anhedonia, and (4) HPA axis regulation and output in male C56Bl/6 mice.

Motor, Somatosensory, Viscerosensory and Metabolic Impairments in a Heterozygous Female Rat Model of Rett Syndrome.

Rett Syndrome (RTT), an autism-related disorder caused by mutation of the X-linked Methyl CpG-binding Protein 2 () gene, is characterized by severe cognitive and intellectual deficits. While cognitive deficits are well-documented in humans and rodent models, impairments of sensory, motor and metabolic functions also occur but remain poorly understood. To better understand non-cognitive deficits in RTT, we studied female rats heterozygous for mutation (); unlike commonly used male rodent models, this more closely approximates human RTT where males rarely survive.

Neonatal maternal separation increases susceptibility to experimental colitis and acute stress exposure in male mice.

Experiencing early life stress can result in maladjusted stress response via dysregulation of the hypothalamic-pituitary-adrenal axis and serves as a risk factor for developing chronic pelvic pain disorders. We investigated whether neonatal maternal separation (NMS) would increase susceptibility to experimental colitis or exposure to acute or chronic stress. Male mice underwent NMS from postnatal day 1-21 and as adults were assessed for open field behavior, hindpaw sensitivity, and visceromotor response (VMR) to colorectal distension (CRD).

Urinary bladder hypersensitivity and dysfunction in female mice following early life and adult stress.

Early adverse events have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. Despite high clinical relevance and reports of stress-related symptom exacerbation, animal models investigating the contribution of early life stress to female urological pain are lacking. We examined the impact of neonatal maternal separation (NMS) on bladder sensitivity and visceral neuroimmune status both prior-to, and following, water avoidance stress (WAS) in adult female mice.

Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has a lifetime prevalence of 14% and is the most common urological diagnosis for men under the age of 50, yet it is the least understood and studied chronic pelvic pain disorder. A significant subset of patients with chronic pelvic pain report having experienced early life stress or abuse, which can markedly affect the functioning and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Mast cell activation, which has been shown to be increased in both urine and expressed prostatic secretions of CP/CPPS patients, is partially regulated by downstream activation of the HPA axis.

Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic-pituitary-adrenal axis output in female mice.

Experiencing early life stress or injury increases a woman's likelihood of developing vulvodynia and concomitant dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate the outcome of neonatal vaginal irritation (NVI), female mouse pups were administered intravaginal zymosan on postnatal days 8 and 10 and were assessed as adults for vaginal hypersensitivity by measuring the visceromotor response to vaginal balloon distension (VBD). Western blotting and calcium imaging were performed to measure transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) in the vagina and innervating primary sensory neurons.