**1. Introduction**

Visceral hyperalgesia (VH) is a pathological state of inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS) or other functional bowel disorders, in which sensory threshold for abdominal pain and discomfort decreases due to tissue injury, inflammation, and persistent exposure of tissues/organ to noxious stimuli. In this state, the continuous release of inflammatory mediators results in sensitization of primary afferents and abdominal pain, both during the acute flare of diseases and their remission [1, 2]. Despite several proposed factors including inflammation, psychology and aberrant sensory-motor function of the gut contribute to peripheral and central sensitization [3], the exact underlying mechanism of VH has not been

fully elucidated. The cell-membrane protease-activated receptor-2 (PAR-2) mediates calcitonin gene-related peptide (CGRP) release, and their associated roles in neurogenic inflammation-induced sensitization could be of great interest for the researchers to address this persistent nature of VH.

A G-protein coupled receptor PAR-2, distributed throughout the gastrointestinal (GI) tract, is activated particularly by proteases such as tryptase, trypsin, and cathepsin-S [4–6]. PAR-2 activation on several cells (epithelial cells, endothelial cells, neutrophils, macrophages, monocytes, mast cells, fibroblasts, neurons, dendritic cells, lymphocytes, etc.) could lead to the release of cytokines, chemokines, prostaglandins [7], as well as CGRP and substance-P (SP) in the enteric neurons and afferent neurons [8, 9]. Numerous reports indicated the diverse SP and CGRP expressions within the dorsal root ganglia (DRG) and spinal neurons during colitis and ileitis [10–15]. The expressions of SP and CGRP within the gut not only excite extrinsic afferents but also perpetuate the central transmission of nociceptive traffic between afferent neurons and higher-order neurons in the spinal cord and brainstem [16]. Thus, it is worthwhile to consider the key role of PAR-2 in the release of CGRP, which subsequently triggers neurogenic inflammation mediated VH.

Currently, the pharmacotherapy for VH is unsatisfactory because of its unknown precise mechanism. Earlier study suggests that the blockade of PAR-2at the periphery and/or the inhibition of luminal protease activity may be of interest for treating the VH [17]. Likewise, the administration of CGRP antagonists inhibits VH in animals [18, 19]. Therefore, the blockade or antagonism of either PAR-2 or CGRP may be a promising therapeutic target for VH. This review chapter explores the important roles of PAR-2 and PAR-2-mediated CGRP during inflammatory gut and their antagonism or blockade for the treatment of VH.
