The pronociceptive effect of proteinase-activated receptor-4 stimulation in rat knee joints is dependent on mast cell activation

Abstract

Proteinase-activated receptor-4 (PAR(4)) is a G-protein-coupled receptor activated by serine proteinases released during tissue repair and inflammation. We have previously shown that PAR(4) activation sensitises articular primary afferents leading to joint pain. This study examined whether mast cells contribute to this PAR(4)-induced sensitisation and consequent heightened pain behaviour. The expression of PAR(4) on synovial mast cells was confirmed with immunofluorescent staining of rat knee joint sections. Electrophysiological recordings were made from joint primary afferents in male Wistar rats during both nonnoxious and noxious rotations of the knee. Afferent firing rate was recorded for 15 minutes after close intra-arterial injection of 10(-9) to 10(-5)mol of the PAR(4) activating peptide, AYPGKF-NH(2), or the inactive peptide, YAPGKF-NH(2) (100-μl bolus). Rats were either naive or pretreated with the mast cell stabilise, cromolyn (20mg/kg). Mechanical withdrawal thresholds were determined using a dynamic planter aesthesiometer and weight bearing determined using an incapacitance tester. These behavioural measurements were taken before and after intra-articular AYPGKF-NH(2), or the inactive peptide, YAPGKF-NH(2) (100μg). Local administration of AYPGKF-NH(2) caused a significant increase in joint primary afferent firing rate and pain behaviour compared with the control peptide YAPGKF-NH(2). These effects were blocked by pretreatment with cromolyn. These data reveal that PAR(4) is expressed on synovial mast cells and the activation of PAR(4) has a pronociceptive effect that is dependent on mast cell activation. Proteinase-activated receptor-4 is expressed on synovial mast cells, and the activation of Proteinase-activated receptor-4 has a pronociceptive effect that is dependent on mast cell activation.

Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

“…Since CCL2 is well known to be implicated in rheumatoid arthritis [98], a role for a PAR 1 -EGFR transactivation interplay in this inflammatory disease has been suggested. Further, both PARs 2 and 4 have been implicated in arthritis pain as well as inflammation [99-102]. In an adjuvant model of arthritis, PAR 2 has been found to play a critical role [103], but the precise mechanisms whereby PAR 2 promotes joint inflammation, possibly involving RTK transactivation are not yet known.…”

Increased Expression of Protease-Activated Receptor 2 and 4 Within Dorsal Root Ganglia in a Rat Model of Bone Cancer Pain

“…PAR4 has been identified as one of the most important nociceptive mediators in the control of pain and inflammation in dorsal root ganglion (DRG) sensory neurons (McDougall et al 2009;Russell et al 2010Russell et al , 2011. Accumulating evidence confirms that PAR4 messenger RNA (mRNA) and protein are expressed in most of nociceptive neurons in DRG Vellani et al 2010;Zhu et al 2005) and the majority of these cells are peptidergic that are marked by CGRP positivity (Asfaha et al 2007).…”

Silencing of protease‐activated receptors attenuates synovitis and cartilage damage following a joint bleed in haemophilic mice

“…In addition, stimulation of PAR2 results in joint swelling, synovial hyperplasia and cartilage damage, whereas synovial pro‐inflammatory cytokine production is reduced with antagonism of PAR2 . Finally, PAR4 stimulation results in joint pain and inflammation . Regarding this, it is interesting to see that in our study murine synovial PAR1, PAR2 and PAR3, murine chondrocyte PAR2 and PAR4, human synovial PAR1 and human chondrocyte PAR4 expression was elevated.…”