Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

Abstract

Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS). Early life stress (ELS) is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for stress-induced exacerbation of chronic visceral pain. Additionally, we will review the importance of specific experimental models of adult stress and ELS in enhancing our understanding of the basic molecular mechanisms of pain processing.

Walking the Tightrope: A Proposed Model of Chronic Pain and Stress

“…A behavioral experiment conducted by our group (Sieberg et al, 2018) found that 1. the effects of long-term spared nerve injury (SNI) and life-long stress are not markedly different to SNI alone, suggesting that ongoing pain derived from nerve injury is the primary driver of the prominent anxiety-like phenotypes witnessed in the mice examined and 2. long-term SNI and chronic stress were almost equivalent in increasing plasma corticosterone levels, which suggests similar levels of signaling through this endogenous stress system for each condition. Glutamate is known to be the primary excitatory neurotransmitter modulating nociceptive networks, and Glt1 is critical in pain signaling termination (Greenwood-Van Meerveld and Johnson, 2017). Chronic emotional stress results in hyperalgesia that correlates with altered CNS glutamate processing (Greenwood-Van Meerveld and Johnson, 2017).…”

Critical evaluation of animal models of visceral pain for therapeutics development: A focus on irritable bowel syndrome

“…The visceral pain subgroup discussed multiple rodent models of visceral hypersensitivity induced following neonatal or adult stressors (acute or chronic, homotypic, or heterotypic), enemas of irritants (dilute acetic acid, zymogen, deoxycholic acid), inflammation (or postinflammatory), manipulation of central signaling, or from knockdown or knockout of genes. The reader is referred to a number of excellent and recent reviews describing in detail rodent models of visceral hypersensitivity . The visceral pain subgroup considered that one model in particular was worthy of being considered for screening novel therapeutics: the intracolonic trinitrobenzene sulfonic acid (TNBS) pretreatment model.…”

“…The reader is referred to a number of excellent and recent reviews describing in detail rodent models of visceral hypersensitivity. 12,27,28 The visceral pain subgroup considered that one model in particular was worthy of being considered for screening novel therapeutics: the intracolonic trinitrobenzene sulfonic acid (TNBS) pretreatment model. This recommendation is in contrast to recommendations of the 2016 National Institutes of Health (NIH) Functional Bowel Disorder workgroup whose goal was to identify animal models that could be employed for basic discovery into the etiology of IBS, 15 while the NINDs subgroup was tasked with identifying the best model for discovery of new therapeutics.…”

Abdominal pain related to pathology of peripheral nervous system

“…Первичная гипералгезия возникает непосредственно в повреждённом участке вследствие сенсибилизации рецепторов биологически активными веществами (нейроактивными пептидами, кининами, простагландинами, лейкотриенами). Вторичная гипералгезия и аллодиния связаны с нейропластическими изменениями в ЦНС («болевой памятью» с изменением чувствительности глютаматергических NMDA-и AMPA-рецепторов) [6,7]; область восприятия боли выходит за границы тканевого повреждения и области иннервации поражённого нерва.…”