Protease-activated receptor-2 (PAR-2)-related peptides induce tear secretion in rats: involvement of PAR-2 and non-PAR-2 mechanisms

Protease-activated receptor-2 (PAR-2) plays an extensive role in the regulation of digestive exocrine secretion. The present study examined whether PAR-2-related Peptides could modulate tear secretion in rats and analyzed the underlying mechanisms. SLIGRL-NH(2), a PAR-2-activating peptide (PAR-2-AP) derived from mouse/rat PAR-2, when administered i.v. in combination with amastatin, an Aminopeptidase Inhibitor, evoked tear secretion, whereas LRGILS-NH(2), a PAR-2-inactive reversed peptide, had no such effect. In contrast, LSIGRL-NH(2), a partially reversed peptide known to be inactive with PAR-2, caused tear secretion equivalent to the effect of SLIGRL-NH(2). SLIGKV-NH(2), a human-derived PAR-2-AP, also induced significant tear secretion though to a lesser extent, whereas neither VKGILS-NH(2), a reversed peptide, nor LSIGKV-NH(2), a partially reversed peptide, produced any secretion. In desensitization experiments, after the first dose of SLIGRL-NH(2), the second dose of SLIGRL-NH(2) produced no tear secretion, whereas the response to LSIGRL-NH(2) was only partially inhibited by preadministration of SLIGRL-NH(2). Preadministration of LSIGRL-NH(2) abolished the response to subsequently administered LSIGRL-NH(2) but not SLIGRL-NH(2). The tear secretion induced by LSIGRL-NH(2) but not by PAR-2-APs was blocked by atropine or hexamethonium. Mast cell depletion due to repeated doses of compound 48/80 did not alter the effect of SLIGRL-NH(2) or LSIGRL-NH(2). Finally, IGRL-NH(2), a possible core structure of LSIGRL-NH(2), triggered tear secretion in an atropine-reversible manner. Our findings suggest that the PAR-2-APs SLIGRL-NH(2) and SLIGKV-NH(2) cause tear secretion, most likely via PAR-2 and that LSIGRL-NH(2), a PAR-2-inactive peptide, and IGRL-NH(2), its key structure, trigger tear secretion by stimulating parasympathetic nerves via an unidentified target molecule.