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This Article Full Text Full Text (PDF) All Versions of this Article: 102/1/312    most recent 91117.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Fujita, T. Articles by Kumamoto, E. PubMed PubMed Citation Articles by Fujita, T. Articles by Kumamoto, E.

Proteinase-Activated Receptor-1 Activation Presynaptically Enhances Spontaneous Glutamatergic Excitatory Transmission in Adult Rat Substantia Gelatinosa Neurons

Department of Physiology, Saga Medical School, Saga 849-8501, Japan

Submitted 7 October 2008; accepted in final form 30 April 2009

Proteinase-activated receptors (PARs) have a unique activation mechanism in that a proteolytically exposed N-terminal region acts as a tethered ligand. A potential impact of PAR on sensory processing has not been fully examined yet. Here we report that synthetic peptides with sequences corresponding to PAR ligands enhance glutamatergic excitatory transmission in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole cell patch-clamp technique. The frequency of spontaneous excitatory postsynaptic current (EPSC) was increased by PAR-1 agonist SFLLRN-NH₂ (by 47% at 1 µM) with small increases by PAR-2 and -4 agonists (SLIGKV-NH₂ and GYPGQV-OH, respectively; at >3 µM); there was no change in its amplitude or in holding current at –70 mV. The PAR-1 peptide action was inhibited by PAR-1 antagonist YFLLRNP-OH. TFLLR-NH₂, an agonist which is more selective to PAR-1 than SFLLRN-NH₂, dose-dependently increased spontaneous EPSC frequency (EC₅₀ = 0.32 µM). A similar presynaptic effect was produced by PAR-1 activating proteinase thrombin in a manner sensitive to YFLLRNP-OH. The PAR-1 peptide action was resistant to tetrodotoxin and inhibited in Ca²⁺-free solution. Primary-afferent monosynaptically evoked EPSC amplitudes were unaffected by PAR-1 agonist. These results indicate that PAR-1 activation increases the spontaneous release of L-glutamate onto SG neurons from nerve terminals in a manner dependent on extracellular Ca²⁺. Considering that sensory processing within the SG plays a pivotal role in regulating nociceptive transmission to the spinal dorsal horn, the PAR-1-mediated glutamatergic transmission enhancement could be involved in a positive modulation of nociceptive transmission.