The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments

Abstract

Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1 receptors, serotonin (5-hydrodytryptamine) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH. (J Neurogastroenterol Motil 2016;22:558-574)

Mechanisms of Stress-induced Visceral Pain

“…19,20 In this review we will discuss the hypothesis that visceral pain disorders result from abnormalities of the brain-gut axis due to "multiple hits" which include external risk factors such as abuse history and chronic psychological stress in adulthood which together are capable of sensitizing the stress response system to cause alterations in no-An important aspect to enhancing our understanding of IBS pathophysiology is the knowledge that IBS patients exhibit visceral hypersensitivity characterized by hyperalgesia and allodynia in a subset of IBS patients ranging from 33-90% of patients with IBS depending on the study. [37][38][39][40][41][42] Although the cause of visceral hypersensitivity is unknown, clinical studies have shown that chronic stress worsens IBS symptomatology and ELS serves as a risk factor for IBS. [43][44][45][46] The sympatho-medullary and the HPA axes are activated by exposure to stress; the sympatho-medullary axis releases epinephrine from the adrenal medulla, to allow the organism to "fight" or "flee" from a threat, whilst activation of the HPA axis releases cortisol (or corticosterone [CORT] in rodents) from the adrenal cortex to mobilize reserves of glucose with the goal of replenishing the expended sympatho-medullary system.…”

Maternal Separation Induced Visceral Hypersensitivity from Childhood to Adulthood

“…[5][6][7][8][9] Visceral hypersensitivity is one important pathophysiological mechanism in the generation of IBS. 10,11 Many previous experimental studies found that EALs such as maternal separation (MS) can induce adult visceral hypersensitivity. 5,6,12 However, the effect of EALs on the different age stages from childhood to adulthood is not yet clear.…”

Роль Вісцеральної Гіперчутливості В Розвитку Синдрому Подразненого Кишечника

“…Как известно, при отсутствии патологических изменений обычное растяжение или сокращение полого органа не ощущается человеком. Нарушенная чувствитель-ность в ответ на нормальные физиологические стиму-лы рассматривается как ВГЧ [1]. При наличии ВГЧ у пациентов с СРК отмечается усиленная перцепция (ощущение, восприятие) в ответ на механические воз-действия на кишечник, что больным воспринимается как боль или дискомфорт в животе [2].…”

“…Гипералгезия -это состояние, при котором импульсы, которые могут вы-звать в обычных условиях боль, воспринимаются как более интенсивная боль. Аллодиния -это состояние, при котором боль отмечается из-за импульсов, не спо-собных в обычных условиях вызывать болевые ощу-щения [1]. Таким образом, у больных с СРК при ВГЧ отмечается сниженный порог восприятия импульсов из кишечника.…”

“…Однако дальнейшие исследования показали, что ВГЧ может наблюдаться по всему кишечнику и в более прокси-мальных отделах гастроинтестинального тракта. По-добные проявления ВГЧ также могут отмечаться и со стороны желудка, что наблюдается при функциональ-ной диспепсии [1].…”