**4. Role of PAR-2 in VH**

PAR-2 activation in GI resident cells such as MCs, macrophages, or neutrophils induces the release of tiny amounts of inflammatory mediators that sensitizes primary afferents. It regulates vascular tone and causes immense pro- or antiinflammatory as well as pro-nociceptive effects in somatic or visceral pain [78]. PAR-2 expressed at the peripheral afferent neurons is more importantly involved in inflammation-induced VH [29, 30]. The glial cells of the enteric nervous system play pivotal roles in neuroimmune interactions and modulate enteric neurotransmission, inflammation, and intestinal barrier functions as they express receptors for purines and contain precursors for neurotransmitters such as GABA and NO. They can produce cytokines (TNF-α, IL-1β, IL-6), NGF, and neuropeptides (NK-1, SP, CGRP) after their activation. Both PAR-2 and proinflammatory cytokines impair the epithelial barrier by decreasing tight junction protein expression and consequently facilitate the entry of luminal aggressors perpetuating inflammation and pain [9].

PAR-2 expressed in enterocytes increases permeability, which is linked with the immune activation and generation of VH [25, 79]. It is found that PAR-2 agonists evoke the transient depolarization of submucosal enteric neurons with long-lasting hyperexcitability in guinea pigs [80]. Similarly, intracolonically administered PAR-2 agonist (SLIGRL-NH2, 100 μg/mouse) increased intestinal permeability and VH in mice [81]. The intracolonic administration of subinflammatory doses of PAR-2-agonist led to prolonging the VH in response to CRD in rats [78]. PAR-2 activation on enteric neurons is also directly responsible for the development of VH as it conveys nociceptive signals for the excitability of submucosal neurons, colonic projections of DRG, and jejunal afferent neurons [7]. Shi et al. [82] reported PAR-2 activation and higher CGRP levels in the serum and colonic tissue during VH in a rat model of IBS. Accumulating set of evidence suggests that protease activity is remarkably prominent in diarrheic-IBS and UC patients. The fecal supernatant or colonic biopsies from these patients when infused intracolonally into rodents resulted in higher intestinal permeability, mucosal inflammation, and subsequent VH through a PAR-2 activation mechanism [83–86], while the same treatment failed to cause the VH in the PAR-2 knockout mice [83]. **Table 1** summarizes the findings of preclinical studies that intervened in the effects of PAR-2 on underlying VH.



*Intervention of PAR-2 Mediated CGRP in Animal Model of Visceral Hyperalgesia DOI: http://dx.doi.org/10.5772/intechopen.106859*

#### **Table 1.**

*Knock-out; PAR-2, Protease-activated receptor-2.*

*Preclinical studies investigating the effects of protease activated receptor-2 on visceral hyperalgesia.*

Currently, the role of cathepsin-S is considered insightful because it activates spinal nociceptive neurons through a PAR-2-dependent mechanism and amplifies VH. Over the years, studies reported that cathepsin-S released from spinal microglial cells during nerve injury or colitis secretes fractalkine, thereby intensifying and maintaining the chronic pain [91, 92].
