The Role of Protease-Activated Receptor Type 2 in Nociceptive Signaling and Pain

Abstract

Protease-activated receptors (PARs) belong to the G-protein-coupled receptor family, that are expressed in many body tissues especially in different epithelial cells, mast cells and also in neurons and astrocytes. PARs play different physiological roles according to the location of their expression. Increased evidence supports the importance of PARs activation during nociceptive signaling and in the development of chronic pain states. This short review focuses on the role of PAR2 receptors in nociceptive transmission with the emphasis on the modulation at the spinal cord level. PAR2 are cleaved and subsequently activated by endogenous proteases such as tryptase and trypsin. In vivo, peripheral and intrathecal administration of PAR2 agonists induces thermal and mechanical hypersensitivity that is thought to be mediated by PAR2-induced release of pronociceptive neuropeptides and modulation of different receptors. PAR2 activation leads also to sensitization of transient receptor potential channels (TRP) that are crucial for nociceptive signaling and modulation. PAR2 receptors may play an important modulatory role in the development and maintenance of different pathological pain states and could represent a potential target for new analgesic treatments.

The regulators of G protein signaling RGS16 and RGS18 inhibit protease‐activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells

“…PAR2 also plays an important role in nociceptive transmission, and therefore, its antagonism contributes to hyperalgesia [51][52][53]. PAR2 signaling has a significant impact on the induction and maintenance of persistent pain, especially in inflammatory, neuropathic, and cancer conditions [54]. Activation of PAR2 triggers the release of numerous inflammatory mediators, such as prostaglandin-, substance P-, and calcitonin-related gene peptides or cytokines, in turn, inducing or modulating pain perception [55][56][57], signifying an important role in pathogenesis.…”

Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

“…As their names suggest, PARs are activated when proteases such as thrombin or trypsin cleave a portion of the receptor, creating a tethered ligand that then acts as an intramolecular agonist for the receptor. PAR1, 2 and 4 have all been implicated in pain, with PAR2 being the most well-studied (Vellani et al, 2010;Tillu et al, 2015;Mrozkova et al, 2016). PAR3's function, however, remains elusive, with neither the ligand nor mode of action of this receptor known.…”

The mechanisms of protease-activated receptor 2 in mediating pain behaviors through nonselective cation channel signaling

“…The close relationship between P2 × 3 and the pain-sensing system and the specific actions of P2 × 3 on pain sensation attract us to explore P2 × 3 as a novel potential therapeutic target on relieving pain. Sensitization of TRPV1 and TRPA1 via PLC and PKC kinases is correlated with the role of PAR2-mediated nociceptive signaling and pain has been recognized recently [74]. In the present study, both in vitro model of DRG with PAR2 agonist SL-NH2 challenge and SL-NH2-induced pain rat model were used to investigate the relationship between PAR2 activation and nonselective cation channels in mediating pain.…”