**5. Role of PAR-2 in pain transmission**

Proteases directly activate PAR-2 as well as assist other pronociceptive mediators for the subsequent sensitization of afferent fibers [83]. **Figure 1** illustrates the important role of PAR-2 in pain transmission during GI disorders. PAR-2 activation on afferent neurons leads to specific calcium signals that could participate in conveying pain messages [93]. Elmariah et al. [6] reported that cathepsin-S played a role in molecular signaling either alone or together with activated PAR-2. Activation of PAR-2 on DRG by its agonists enhances potassium chloride ions and the capsaicin (TRPV-1 agonist) evoked release of CGRP [8, 94]. Protease-activated receptor-1 and PAR-2 on enteric afferent fibers facilitate nociceptive input to the CNS, while spinal PAR-2 activation aggravates pain behaviors [21]. These findings strongly suggest that visceral activation of PAR-2 has an important role in sensitizing the second-order neurons at spinal level.

#### **Figure 1.**

*Role of PAR-2 in pain transmission. (a) Peripheral sensitization. PAR-2 is activated by proteases released from inflammatory and immune cells as well as from mediators of the intestinal lumen. Proteases sensitize neurons to innocuous stimuli. After stimulation, TRPV-1 depolarizes sensory neurons either directly or indirectly to initiate the release of SP and CGRP from the afferent terminals. PAR-2 activation on afferent neurons leads to specific calcium signals. (b) Primary afferent fiber. Pain signal is transmitted along primary afferent fibers to the spinal dorsal horn and subsequently to the brain. (c) Central sensitization. Persistent small-afferent input leads to a central sensitization associated with local release of SP and CGRP. PAR-2, protease-activated receptor-2;TRP, Transient Receptor Potential; Ca2+, calcium ion; SP, substance-P; CGRP, calcitonin gene-related peptide;TRPV-1, Transient Receptor Potential Vanilloid subtype-1.*
