Protease‐activated receptor‐4: a novel mechanism of inflammatory pain modulation

Background and purpose: Protease‐activated receptor‐4 (PAR 4 ), the most recently discovered member of the PARs family, is activated by thrombin, trypsin and cathepsin G, but can also be selectively activated by small synthetic peptides (PAR 4 ‐activating peptide, PAR 4 ‐AP). PAR 4 is considered a potent mediator of platelet activation and inflammation. As both PAR 1 and PAR 2 have been implicated in the modulation of nociceptive mechanisms, we investigated the expression of PAR 4 in sensory neurons and the effects of its selective activation on nociception. Experimental approach and key results: We demonstrated the expression of PAR 4 in sensory neurons isolated from rat dorsal root ganglia by reverse transcription‐polymerase chain reaction and immunofluorescence. We found that PAR 4 colocalized with calcitonin gene‐related peptide and substance P. We also showed that a selective PAR 4 ‐AP was able to inhibit calcium mobilization evoked by KCl and capsaicin in rat sensory neurons. Moreover, the intraplantar injection of a PAR 4 ‐AP significantly increased nociceptive threshold in response to thermal and mechanical noxious stimuli, while a PAR 4 inactive control peptide had no effect. The anti‐nociceptive effects of the PAR 4 ‐AP were dose‐dependent and occurred at doses below the threshold needed to cause inflammation. Finally, co‐injection of the PAR 4 ‐AP with carrageenan significantly reduced the carrageenan‐induced inflammatory hyperalgesia and allodynia, but had no effect on inflammatory parameters such as oedema and granulocyte infiltration. Conclusions and implications: Taken together, these results identified PAR 4 as a novel potential endogenous analgesic factor, which can modulate nociceptive responses in normal and inflammatory conditions. British Journal of Pharmacology (2007) 150 , 176–185. doi: 10.1038/sj.bjp.0706975