RESUMO
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.
Assuntos
Artrite/patologia , Receptor PAR-2/análise , Transtornos da Articulação Temporomandibular/patologia , Animais , Artropatia Neurogênica/patologia , Imunidade Inata/imunologia , Injeções Intra-Articulares , Masculino , Fibras Nervosas/patologia , Neuroimunomodulação/imunologia , Antagonistas dos Receptores de Neurocinina-1 , Neurônios/patologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Medição da Dor , Piperidinas/farmacologia , Plasma , Quinuclidinas/farmacologia , Ratos , Ratos Wistar , Receptor PAR-2/agonistas , Células Receptoras Sensoriais/patologia , Substância P/análise , Articulação Temporomandibular/inervação , Gânglio Trigeminal/patologia , Tripsina/administração & dosagem , Tripsina/farmacologia , Ubiquitina Tiolesterase/análiseRESUMO
BACKGROUND AND PURPOSE: Recent findings suggest that the noxious gas H(2)S is produced endogenously, and that physiological concentrations of H(2)S are able to modulate pain and inflammation in rodents. This study was undertaken to evaluate the ability of endogenous and exogenous H(2)S to modulate carrageenan-induced synovitis in the rat knee. EXPERIMENTAL APPROACH: Synovitis was induced in Wistar rats by intra-articular injection of carrageenan into the knee joint. Sixty minutes prior to carrageenan injection, the rats were pretreated with indomethacin, an inhibitor of H(2)S formation (DL-propargylglycine) or an H(2)S donor [Lawesson's reagent (LR)]. KEY RESULTS: Injection of carrageenan evoked knee inflammation, pain as characterized by impaired gait, secondary tactile allodynia of the ipsilateral hindpaw, joint swelling, histological changes, inflammatory cell infiltration, increased synovial myeloperoxidase, protein nitrotyrosine residues, inducible NOS (iNOS) activity and NO production. Pretreatment with LR or indomethacin significantly attenuated the pain responses, and all the inflammatory and biochemical changes, except for the increased iNOS activity, NO production and 3-NT. Propargylglycine pretreatment potentiated synovial iNOS activity (and NO production), and enhanced macrophage infiltration, but had no effect on other inflammatory parameters. CONCLUSIONS AND IMPLICATIONS: Whereas exogenous H(2)S delivered to the knee joint can produce a significant anti-inflammatory and anti-nociceptive effect, locally produced H(2)S exerts little immunomodulatory effect. These data further support the development and use of H(2)S donors as potential alternatives (or complementary therapies) to the available anti-inflammatory compounds used for treatment of joint inflammation or relief of its symptoms.