Suppression of pancreatitis-related allodynia/hyperalgesia by proteinase-activated receptor-2 in mice

Abstract

1 Proteinase-activated receptor-2 (PAR2), a receptor activated by trypsin and tryptase, is abundantly expressed in the gastrointestinal tract including the C-fiber terminal, and might play a role in processing of visceral pain. In the present study, we examined and characterized the roles of PAR2 in pancreatitis-related abdominal hyperalgesia/allodynia in mice. 2 Caerulein, administered i.p. once, caused a small increase in abdominal sensitivity to stimulation with von Frey hairs, without causing pancreatitis, in PAR2-knockout (KO) mice, but not wild-type (WT) mice. 3 Caerulein, given hourly six times in total, caused more profound abdominal hyperalgesia/allodynia in PAR2-KO mice, as compared with WT mice, although no significant differences were detected in the severity of pancreatitis between the KO and WT animals. 4 The PAR2-activating peptide, 2-furoyl-LIGRL-NH(2), coadministered repeatedly with caerulein six times in total, abolished the caerulein-evoked abdominal hyperalgesia/allodynia in WT, but not PAR2-KO, mice. Repeated doses of 2-furoyl-LIGRL-NH(2) moderately attenuated the severity of caerulein-induced pancreatitis in WT animals. 5 Our data from experiments using PAR2-KO mice provide evidence that PAR2 functions to attenuate pancreatitis-related abdominal hyperalgesia/allodynia without affecting pancreatitis itself, although the PAR2AP applied exogenously is not only antinociceptive but also anti-inflammatory.

Figure 1

Caerulein-evoked abdominal mechanical allodynia/hyperalgesia in ddY mice. Caerulein was administered i.p. hourly six times in total to ddY mice. n=11. ns, not significant.

Figure 2

Caerulein-evoked abdominal mechanical allodynia/hyperalgesia in WT and PAR2-KO mice of C57BL/6 background. Caerulein was administered i.p. once (a) or hourly six times in total (b) to WT and PAR2-KO mice of C57BL/6 background. n=6 (b) or 14–20 (a). ns, not significant. KO, PAR2-KO.

Figure 3

Severity of caerulein-evoked pancreatitis in WT and PAR2-KO mice of C57BL/6 background. Caerulein was administered i.p. hourly six times in total or once to WT and PAR2-KO mice of C57BL/6 background. The severity of pancreatitis was evaluated by increased plasma amylase activity (a), increased pancreatic wet weight (b) and morphological scoring of pancreatic sections (c). n=4–6. ns, not significant. KO, PAR2-KO.

Figure 4

Effect of repeated administration of the PAR2AP on caerulein-evoked abdominal mechanical allodynia/hyperalgesia in WT or PAR2-KO mice of C57BL/6 background. The PAR2AP, 2-furoyl-LIGRL-NH₂ (2f-LIGRL-NH₂), at 0.1 μmol kg⁻¹ was coadministered i.p. hourly with caerulein six times in total to WT or PAR2-KO mice. KO, PAR2-KO. n=5–7. ns, not significant.

Figure 5

Effect of repeated administration of the PAR2AP on caerulein-evoked pancreatitis in WT mice of C57BL/6 background. (a) and (b) Effects of 2f-LIGRL-NH₂ on increased plasma amylase activity (a) and pancreatic wet weight (b) in the animals. n=6–7. (c) Typical microphotographs of pancreatic tissues in the mice that received 6 hourly administration of caerulein alone and in combination with 2f-LIGRL-NH₂. Arrows indicate acinar cell death. (d) Morphological scoring of pancreatic sections from the mice treated with caerulein alone or in combination with 2f-LIGRL-NH₂. n=13–14. ns, not significant.