Short communicationThe PAR-1-activating peptide attenuates carrageenan-induced hyperalgesia in rats
Introduction
Protease-activated receptors (PARs) are activated by proteolytic unmasking of the N-terminal cryptic tethered ligand. PAR-1 was cloned as the first thrombin receptor that mediates aggregation of human platelets [8], being followed by discovery of PARs 2–4 in the last decade [3]. PAR-1 is considered to be involved in an inflammatory process, as is PAR-2, a receptor activated by trypsin, tryptase or coagulation factors VIIa and Xa, but not thrombin [1], [3], [4], [5], [6], [7]. Interestingly, PAR-2 is expressed in dorsal root ganglia (DRG) neurons [2], [6] and capable of triggering release of calcitonin gene-related peptide or substance P from slices of the spinal dorsal horn in vitro [6]. A PAR-2 activator, administered by an intraplantar (i.pl.) route, produces thermal hyperalgesia and nociceptive behavior in rats in vivo [2]. DRG neurons are also abundant in PAR-1 [2], [6], whereas PAR-1 activators have neither been found to have an algesic nor analgesic effect. In the present study, we investigated the nociceptive modulation by PAR-1 in the rats with the hyperalgesia induced by carrageenan, a sulfated polysaccharide. Multiple mechanisms including mast cell degranulation and formation of bradykinin, prostanoids and nitric oxide are known to be responsible for this inflammatory hyperalgesia. Here we show, for the first time, that i.pl. administration of PAR-1 activators attenuate carrageenan-induced hyperalgesia in rats, implying an antinociceptive role for the thrombin-PAR-1 pathway under certain conditions.
Section snippets
Materials and methods
Male Wistar rats (7 weeks old) were obtained from Japan SLC. Inc. As described previously [2], mechanical nociceptive threshold was assessed by the responsiveness of the hindpaw to increasing pressure using a meter of analgesia (MK-300 type, Muromachi–Kikai, Japan). Paw thickness was also measured as a parameter of edema formation. After the measurement of baseline threshold, rats received intraplantar (i.pl.) administration of 100 μl of 1% carrageenan dissolved in distilled water, and
Results
Thrombin, when administered i.pl. in a dose-range of 2–50 U per paw to naive rats, did not significantly modify the mechanical nociceptive threshold for 3 h (data not shown). In contrast, i.pl. administration of thrombin at a dose of 5 U per paw markedly enhanced the nociceptive threshold in the rats with the hyperalgesia induced by i.pl. carrageenan, although it failed to produce significant effect at 1–3 U per paw (Fig. 1A). Similarly, the PAR-1-activating peptide TFLLR-NH2 administered i.pl. at
Discussion
The present findings that i.pl. administration of thrombin as well as the specific PAR-1 activator TFLLR-NH2, but not the inactive control peptide FTLLR-NH2, attenuated carrageenan-induced hyperalgesia in the rat, strongly imply an antinociceptive role for PAR-1, at least during inflammatory hyperalgesia. This may be indicative of the role of PAR-1 expressed in DRG neurons [2], [6], although it has to be elucidated whether the effects of PAR-1 activators result from direct activation of
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