piperidines and Arthropathy--Neurogenic

The proteinase-activated receptor 2 (PAR(2)) is a putative therapeutic target for arthritis. We hypothesized that the early pro-inflammatory effects secondary to its activation in the temporomandibular joint (TMJ) are mediated by neurogenic mechanisms. Immunofluorescence analysis revealed a high degree of neurons expressing PAR(2) in retrogradely labeled trigeminal ganglion neurons. Furthermore, PAR(2) immunoreactivity was observed in the lining layer of the TMJ, co-localizing with the neuronal marker PGP9.5 and substance-P-containing peripheral sensory nerve fibers. The intra-articular injection of PAR(2) agonists into the TMJ triggered a dose-dependent increase in plasma extravasation, neutrophil influx, and induction of mechanical allodynia. The pharmacological blockade of natural killer 1 (NK(1)) receptors abolished PAR(2)-induced plasma extravasation and inhibited neutrophil influx and mechanical allodynia. We conclude that PAR(2) activation is pro-inflammatory in the TMJ, through a neurogenic mechanism involving NK(1) receptors. This suggests that PAR(2) is an important component of innate neuro-immune response in the rat TMJ.

Topics: Animals; Arthritis; Arthropathy, Neurogenic; Immunity, Innate; Injections, Intra-Articular; Male; Nerve Fibers; Neuroimmunomodulation; Neurokinin-1 Receptor Antagonists; Neurons; Neutrophil Infiltration; Neutrophils; Oligopeptides; Pain Measurement; Piperidines; Plasma; Quinuclidines; Rats; Rats, Wistar; Receptor, PAR-2; Sensory Receptor Cells; Substance P; Temporomandibular Joint; Temporomandibular Joint Disorders; Trigeminal Ganglion; Trypsin; Ubiquitin Thiolesterase