Postinflammatory visceral sensitivity and pain mechanisms

Abstract  The inflammatory reaction is normally tightly regulated, and as soon as the original insult has been cleared, a resolution phase starts that aims at leading the tissues back to a normal physiological state. However, after intestinal inflammation, a number of patients develop postinflammatory hypersensitivity symptoms, which can be defined as an excessive sensitivity to gut nociceptive stimulation. The pain experienced by those patients has been largely studied in the context of postinfectious intestinal diseases. The mechanisms of postinflammatory persistent visceral pain involve peripheral and central neuroplastic changes, low-grade chronic inflammation that sensitizes visceral afferent pathways and sensitization of non-neuronal resident cells of the gut. Several molecular determinants such as neurokinins, serotonin, proteases and voltage-gated ion channels seem to play a significant role in the control of postinflammatory visceral sensation. This review tries to give insights into the mechanisms of persistent visceral pain following the resolution of intestinal inflammation and tries to identify what needs to be done to further advance the field of postinflammatory hypersensitivity clinical management.     

Protease-activated receptor-4 (PAR4): a role as inhibitor of visceral pain and hypersensitivity

Abstract Protease‐activated receptor‐4 (PAR₄) belongs to the family of receptors activated by the proteolytic cleavage of their extracellular N‐terminal domain and the subsequent binding of the newly released N‐terminus. While largely expressed in the colon, the role of PAR₄ in gut functions has not been defined. We have investigated the effects of PAR₄ agonist on colonic sensations and sensory neuron signalling, and its role in visceral pain. We observed that a single administration of the PAR₄ agonist peptide (AYPGKF‐NH₂), but not the control peptide (YAPGKF‐NH₂) into the colon lumen of mice significantly reduced the visceromotor response to colorectal distension at different pressures of distension. Further, intracolonic administration of the PAR₄ agonist, but not the control peptide, was able to significantly inhibit PAR₂ agonist‐ and transcient receptor potential vanilloid‐4 (TRPV4) agonist‐induced allodynia and hyperalgesia in response to colorectal distension. Protease‐activated receptor‐4 was detected in sensory neurons projecting from the colon, and isolated from the dorsal root ganglia, where it co‐expressed with PAR₂ and TRPV4. In total sensory neurons, PAR₄ agonist exposure inhibited free intracellular calcium mobilization induced by the pro‐nociceptive agonists of PAR₂ and TRPV4. Finally, PAR₄‐deficient mice experienced increased pain behaviour in response to intracolonic administration of mustard oil, compared with wild‐type littermates. These results show that PAR₄ agonists modulate colonic nociceptive response, inhibit colonic hypersensitivity and primary afferent responses to pro‐nociceptive mediators. Endogenous activation of PAR₄ also plays a major role in controlling visceral pain. These results identify PAR₄ as a previously unknown modulator of visceral nociception.