Proteinase-activated receptor-1 agonists attenuate nociception in response to noxious stimuli

Abstract

Proteinase-activated receptor-1 (PAR-1) is activated by thrombin and can be selectively activated by synthetic peptides (PAR-1-activating peptide: PAR-1-AP) corresponding to the receptor's tethered ligand. PAR-1 being expressed by afferent neurons, we investigated the effects of PAR-1 agonists on nociceptive responses to mechanical and thermal noxious stimuli. Intraplantar injection of selective PAR-1-AP increased nociceptive threshold and withdrawal latency, leading to mechanical and thermal analgesia, while control peptide had no effect. Intraplantar injection of thrombin also showed analgesic properties in response to mechanical, but not to thermal stimulus. Co-injection of PAR-1-AP with carrageenan significantly reduced carrageenan-induced mechanical and thermal hyperalgesia, while thrombin reduced carrageenan-induced mechanical but not thermal hyperalgesia. The fact that thrombin is not a selective agonist for PAR-1 may explain the different effects of thrombin and PAR-1-AP. These results identified analgesic properties for selective PAR-1 agonists that can modulate nociceptive response to noxious stimuli in normal and inflammatory conditions.

Figure 1

PAR-1-induced mechanical (a,b) (nociceptive threshold) and thermal (c,d) (withdrawal latency) analgesia, granulocyte infiltration (e) and paw oedema (f) in rats. n=6 – 9 rats per group. For (a), (c) and (f), *P<0.05 compared to basal measurement (time 0) and for (e), *P<0.01 compared to control peptide (RLLFT-NH₂) injected group.

Figure 2

Thrombin-induced mechanical analgesia (a,b) and thermal hyperalgesia (c,d), granulocyte infiltration (e) and paw oedema (f) in rats. n=6 – 9 rats per group. For (a), (c) and (f), *P<0.05 compared to basal measurement (time 0) and for (e), *P<0.01 compared to boiled thrombin injected group.

Figure 3

Effects of intraplantar co-injection of carrageenan and selective PAR-1 agonists and thrombin on carrageenan-induced inflammatory hyperalgesia (a,b), granulocyte infiltration (c) and oedema (d). The changes in nociceptive threshold and withdrawal latency were calculated for each rat as the area under the curve versus time (over a 6 h period) and results are presented as mean±s.e.mean. For all, n=8 rats per group and for (a and b), *P<0.05 compared to carrageenan alone. No significant differences were observed in all groups for (c) and (d).