**Abstract**

Protease-activated receptor-2 (PAR-2) mediates calcitonin gene-related peptide (CGRP) release and collectively plays a crucial role in inflammation-induced visceral hyperalgesia (VH). The present review chapter outlines the substantial advances that elucidated the underlying role of PAR-2 and CGRP in gut inflammation-induced VH and highlights their relevancies in the management of VH. PAR-2 is expressed in a wide range of gastrointestinal cells and its activation on primary afferent nerves by tryptase, trypsin or cathepsin-S is the key mechanism of sensitization during intestinal inflammation. The activated PAR-2 sensitizes transient receptor potential vanilloid subtype-1 receptors and triggers the release of substance-P (SP) and CGRP that are involved both in the transmission and modulation of VH. Approximately, two-thirds of sensory neurons express PAR-2 and 40% of the PAR-2-expressing sensory neurons also express SP and CGRP. Accumulating set of experiments devised that the blockade or antagonism of PAR-2 in inflammatory diseases of the gut depicts double advantages of reducing inflammation and VH. Simultaneously, the uses of CGRP-antagonists inhibit VH and completely suppress PAR-2-agonists-induced intestinal inflammation in animals. However, further study is imperative to improve our understanding of the blockade or antagonism of PAR-2 and CGRP release before its implication as a novel therapeutic for the clinical management of VH in human patients.

**Keywords:** PAR-2, CGRP, intestinal inflammation, visceral hyperalgesia, activation
