**6. Therapies targeting PAR-2 and CGRP for VH**

Researchers have come a long way in terms of understanding and controlling the inflammation-induced VH in experimental animals. An overview of the studies described in the following paragraph is shown in **Table 2**. It is worth mentioning



*Abbreviations: PAR-2, protease-activated receptor-2;TNBS, 2,4,6-trinitrobenzene sulfonic acid; DRG, dorsal root ganglia; NK-1, neurokinin-1;IBS, irritable bowel syndrome; IBS-D, irritable bowel syndrome with diarrhea; CGRP, calcitonin gene-related peptide; α-CGRP, alpha-calcitonin gene-related peptide; β-CGRP, beta-calcitonin gene-related peptide; VH, visceral hyperalgesia; EA, electroacupuncture.*

#### **Table 2.**

*Preclinical studies targeting the antagonism or blockade of PAR-2 and CGRP as a therapeutic strategy for the management of inflammation and visceral hyperalgesia.*

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

that the oral administration of PAR-2-antagonists (GB88) ameliorates acute and chronic colitis induced by PAR-2-agonists and TNBS, respectively, in rats [28]. Several studies have demonstrated that protease inhibitors and PAR-2-antagonists relieve the inflammation and resultant VH in animals [78, 83, 86, 87, 95, 96, 102]. In chronic inflammation and pain syndromes, the blockade of PAR-2 inhibits both pain signals and inflammatory responses [7]. The intraperitoneal administration of PAR-2 antagonist (FSLLRY-NH2, 3 mg/kg daily for 5 days) reversed intestinal permeability and also attenuated VH in PI-IBS mice which confirms the therapeutic potential of PAR-2antagonist in VH [81].

Studies utilizing both CGRP knockout mice and antagonist hCGRP8-37 have confirmed the protective role of CGRP in colitis and devised its insightful roles in hyperalgesia [18, 97, 98, 103]. Intravenously administered hCGRP8-37 attenuated distension-evoked pain responses and completely reversed the sensitization effects in acetic acid-induced acute colitis rats [18]. Julia and Bueno [99] reported that hCGRP8-37 also suppressed the pain in rats provoked by intraperitoneal injection of acetic acid. Furthermore, its intrathecal administration reversed the CGRP expressions and alleviated the VH in both acetic acid-induced acute and TNBS-induced chronic colitis rats [18, 19]. Recently, Noor-Mohammadi et al. [101] reported that the single dose of intraperitoneally administered anti-CGRP, i.e., F(ab')2 fragment antibody attenuated the stress-induced colonic hypersensitivity in rats which confirms the prevailing role of CGRP in persistent visceral pain.

Nowadays, alternative therapies have been attracting attention due to their potential in the treatment of VH. Sun et al. [53] described that electroacupuncture (EA) attenuates VH in rats with diarrheic-IBS by suppressing spinal CGRP. EA therapy also alleviated the VH symptoms through downregulation of the PAR2, SP, and CGRP levels in colon tissues in post-inflammation-IBS rats [90]. Likewise, Deng et al. [100] exhibited that the EA at ST-37 and ST-25 relieved the VH in IBS rats by decreasing the number of MCs and suppressing the expression of PAR-2, TRPV1, CGRP, SP and Try proteins in the colonic tissues. Our recent study also reported the effectiveness of repetitive EA for treating both acute and chronic pain because it down-regulated the PAR-2-mediated CGRP release in the spinal cord [15]. Shi et al. [82] administered Shugan decoction (herbal extracts) intragastrically in rats in IBS model and found that it abolished VH by attenuating the release of PAR-2-mediated CGRP.
