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Protease-activated receptor-2 (PAR₂), primarily involved in inflammation, is highly expressed in limbic regions of the brain such as the hippocampus. Although extracellular proteolysis is involved in normal and stress-related neuronal plasticity associated with learning, memory and inflammatory disease states, little is known about the role of PAR₂ and its physiological agonist, trypsin, in the brain. We show immunohistochemically that trypsin co-localises with tissue plasminogen activator within granular-like structures in PAR₂-positive pyramidal neurons of the rat hippocampus. Central administration of the PAR₂ peptide agonist, SLIGRL, inhibited electrical amygdala kindling-induced epileptogenesis and abolished kindling-induced over-expression of trypsin in the hippocampus. SLIGRL similarly attenuated kindling when administered subcutaneously. Non-enzymatic activation of neuronal PAR₂ using SLIGRL may …