Background & Aims 5-hydroxytryptamine receptor (5-HT₄R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT₄ receptors are expressed in the colonic epithelium and that 5-HT₄R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. Methods Mucosal expression of the 5-HT₄R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT₄R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl⁻ secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT₄R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. Results Mucosal 5-HT₄ receptors were present in the small and large intestines. In the distal colon, 5-HT₄ receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT₄Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl⁻ secretion. Luminal administration of 5-HT₄R agonists accelerated propulsive motility; a 5-HT₄R antagonist blocked this effect. Bath application of 5-HT₄R agonists did not affect motility. Oral or intracolonic administration of 5-HT₄R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT₄R antagonist. Conclusions Mucosal 5-HT₄ receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT₄R agonists. Colon-targeted, intraluminal delivery of 5-HT₄R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.

Beverley Greenwood-Van Meerveld, and Anthony C Johnson. J Neurogastroenterol Motil 2018;24:7-18. https://doi.org/10.5056/jnm17137

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.