RESUMEN
BACKGROUND: Studies have indicated that nearly half of all surgical patients still have inadequate pain relief. Thus, it is crucial to understand the mechanisms involved in postoperative pain in order to better treat it. Thus, the aim of this study was to investigate the involvement of mast cell degranulation, tryptase and its substrate, the protease-activated receptor 2, in a model of postoperative pain in mice. METHODS: We evaluated the effect of the compound 48/80 (to cause mast cell mediator depletion), cromoglycate or ketotifen (mast cell stabilizers), gabexate (tryptase inhibitor) or N3-methylbutyryl-N-6-aminohexanoyl-piperazine (protease-activated receptor 2 antagonist) in a postoperative pain model in mice (n = 5-10). Mast cell degranulation and tryptase activity were also evaluated in the operated tissue (n= 5-8). RESULTS: The pre-treatment with compound 48/80 or ketotifen was able to prevent nociception throughout the postoperative hyperalgesia course (until 5 days after surgery), whereas cromoglycate presented a shorter effect (until 1 day). Gabexate or N3-methylbutyryl-N-6-aminohexanoyl-piperazine also produced a short-lasting effect in preventing postoperative nociception. However, neither gabexate, N3-methylbutyryl-N-6-aminohexanoyl-piperazine nor cromoglycate was capable of reversing nociception when administered after incision. Surgery led to early mast cell degranulation on the incised tissue and increased tryptase activity in tissue perfusates. Cromoglycate fully prevented the tryptase release in the perfusate and the compound 48/80 substantially reduced tryptase activity in the incised tissue. CONCLUSION: Thus, the mast cell degranulation with the subsequent release of tryptase and protease-activated receptor 2 activation are potential targets for the development of novel therapies to prevent, but not reverse, postoperative pain.
Asunto(s)
Mastocitos/metabolismo , Dolor Postoperatorio/etiología , Dolor Postoperatorio/metabolismo , Receptor PAR-2/metabolismo , Triptasas/fisiología , Animales , Degranulación de la Célula/fisiología , Terapia de Inmunosupresión/métodos , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/enzimología , Ratones , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Dolor Postoperatorio/prevención & control , Piperazinas/farmacología , Piperazinas/uso terapéutico , Receptor PAR-2/antagonistas & inhibidores , Receptor PAR-2/fisiología , Triptasas/antagonistas & inhibidoresRESUMEN
It has been demonstrated that trypsin is able to evoke the classical signals of inflammation, mainly via the activation of proteinase-activated receptor-2 (PAR-2). This study was designed to evaluate the inflammatory and nociceptive responses caused by trypsin injection in the mouse paw. Trypsin produced a dose- and time-related paw edema, a response that was markedly reduced in PAR-2-deficient mice compared to wild-type mice, particularly at the early time-points after trypsin injection. In addition, trypsin produced an increase in myeloperoxidase (MPO) activity, which was significantly reduced in PAR-2-deficient mice. The injection of trypsin into the mouse paw also elicited a dose- and time-dependent spontaneous nociception, as well as thermal and mechanical hypernociceptive responses, which were consistently decreased in mice with genetic deletion of PAR-2. Pharmacological evaluation revealed that edema formation and spontaneous nociception caused by trypsin injection in the mouse paw are mediated by a complex range of mediators. Both edema and nociception seem to rely on the production of neuropeptides, probably involving C-fibre activation and vanilloid receptor-1 (TRPV1), besides the stimulation of kinin B(2) receptors. Edematogenic response is also likely related to the production of cyclooxygenase (COX) metabolites, whereas the mast cell activation appears to be greatly associated to spontaneous nociception. Altogether, the present results indicate that trypsin-induced edema and nociception in the mouse paw represent multi-mediated responses that are largely, but not exclusively, related to the activation of PAR-2. These pieces of evidence provide new insights on the role of trypsin in pain and inflammation.
Asunto(s)
Inflamación/inducido químicamente , Nociceptores/efectos de los fármacos , Dolor/fisiopatología , Tripsina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Masculino , Mastocitos/fisiología , Ratones , Nociceptores/fisiología , Receptor de Bradiquinina B2/fisiología , Receptor PAR-2/fisiología , Canales Catiónicos TRPV/fisiologíaRESUMEN
Proteinase-activated receptor-2 (PAR2) belongs to a novel subfamily of G-protein-coupled receptors with seven-transmembrane domains. This receptor is widely distributed throughout the body and seems to be importantly involved in inflammatory processes. PAR2 can be activated by serine proteases such as trypsin, mast cell tryptase, and bacterial proteases, such as gingipain produced by Porphyromonas gingivalis. This review describes the current stage of knowledge of the possible mechanisms that link PAR2 activation with periodontal disease, and proposes future therapeutic strategies to modulate the host response in the treatment of periodontitis.
Asunto(s)
Periodontitis/enzimología , Receptor PAR-2/fisiología , Receptores Proteinasa-Activados/fisiología , Infecciones por Bacteroidaceae/enzimología , Humanos , Inflamación/enzimología , Inflamación/fisiopatología , Periodontitis/fisiopatología , Porphyromonas gingivalis , Receptores Proteinasa-Activados/metabolismoRESUMEN
The intestinal epithelium plays a crucial role in providing a barrier between the external environment and the internal milieu of the body. A compromised mucosal barrier is characteristic of mucosal inflammation and is a key determinant of the development of intestinal diseases such as Crohn's disease and ulcerative colitis. The intestinal epithelium is regularly exposed to serine proteinases and this exposure is enhanced in numerous disease states. Thus, it is important to understand how proteinase-activated receptors (PARs), which are activated by serine proteinases, can affect intestinal epithelial function. This review surveys the data which demonstrate the wide distribution of PARs, particularly PAR-1 and PAR-2, in the gastrointestinal tract and accessory organs, focusing on the epithelium and those cells which communicate with the epithelium to affect its function. PARs have a role in regulating secretion by epithelia of the salivary glands, stomach, pancreas and intestine. In addition, PARs located on subepithelial nerves, fibroblasts and mast cells have important implications for epithelial function. Recent data outline the importance of the cellular site of PAR expression, as PARs expressed on epithelia may have effects that are countered by PARs expressed on other cell types. Finally, PARs and their ability to promote epithelial cell proliferation are discussed in terms of colon cancer.