sb-366791 and Hypersensitivity

Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) receptors in the peripheral nerve endings are implicated in the development of increased sensitivity to mechanical and thermal stimuli, especially during inflammatory states. Both PAR2 and TRPV1 receptors are co-expressed in nociceptive dorsal root ganglion (DRG) neurons on their peripheral endings and also on presynaptic endings in the spinal cord dorsal horn. However, the modulation of nociceptive synaptic transmission in the superficial dorsal horn after activation of PAR2 and their functional coupling with TRPV1 is not clear. To investigate the role of spinal PAR2 activation on nociceptive modulation, intrathecal drug application was used in behavioural experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) were performed on superficial dorsal horn neurons in acute rat spinal cord slices. Intrathecal application of PAR2 activating peptide SLIGKV-NH2 induced thermal hyperalgesia, which was prevented by pretreatment with TRPV1 antagonist SB 366791 and was reduced by protein kinases inhibitor staurosporine. Patch-clamp experiments revealed robust decrease of mEPSC frequency (62.8 ± 4.9%), increase of sEPSC frequency (127.0 ± 5.9%) and eEPSC amplitude (126.9 ± 12.0%) in dorsal horn neurons after acute SLIGKV-NH2 application. All these EPSC changes, induced by PAR2 activation, were prevented by SB 366791 and staurosporine pretreatment. Our results demonstrate an important role of spinal PAR2 receptors in modulation of nociceptive transmission in the spinal cord dorsal horn at least partially mediated by activation of presynaptic TRPV1 receptors. The functional coupling between the PAR2 and TRPV1 receptors on the central branches of DRG neurons may be important especially during different pathological states when it may enhance pain perception.

Topics: Anilides; Animals; Behavior, Animal; Cinnamates; Excitatory Postsynaptic Potentials; Hyperalgesia; Hypersensitivity; In Vitro Techniques; Male; Oligopeptides; Patch-Clamp Techniques; Posterior Horn Cells; Protein Kinase Inhibitors; Rats; Rats, Wistar; Receptor, PAR-2; Spinal Cord; Staurosporine; Synaptic Transmission; TRPV Cation Channels

The activation of C-fibers in the airways induces coughing, mucus production and bronchoconstriction, which are also symptoms of airway diseases. In this study, we evaluated the role of the C-fibers and the TRPV1 (transient receptor potential vanilloid 1) receptor in an experimental mouse model of allergic airway inflammation. To study the role of C-fibers, we either degenerated the C-fibers persistently (capsaicin administration in neonate mice) or transiently (capsaicin administration in adult mice). No alteration was observed in eosinophil recruitment to the bronchoalveolar lavage fluid in animals treated with capsaicin in the neonatal period. However, in adult animals, capsaicin treatment after the first ovalbumin challenge (in the establishment of the inflammatory process) decreased the eosinophil numbers. This effect was more pronounced in adult animals treated with capsaicin before beginning the ovalbumin immunization (in the development of the inflammatory process). In addition, interleukin (IL)-5 and chemokine ligand 11 (CCL11) levels in the bronchoalveolar lavage fluid, as well as P-selectin expression and p65 nuclear factor κB (NF-κB) activation in the lung were also decreased. No alterations were observed in the IL-10 and IL-13 levels. Next we determined the effect of TRPV1 receptor blockade on allergic airway inflammation. SB366791 administrated in mice by intraperitoneal (500μg/kg) or intranasal (0.1, 1 or 10nmol/site) route failed to decrease eosinophil recruitment to the bronchoalveolar lavage fluid or alter any other metrics cited above. Thus, the present results confirm and extend previous data supporting the involvement of C-fibers, but not the TRPV1 receptor, in allergic airway inflammation.

Topics: Allergens; Anilides; Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Capsaicin; Cell Count; Cinnamates; Cytokines; Female; Gene Expression Regulation; Hypersensitivity; Immunization; Inflammation; Leukocytes; Lung; Mice; Mice, Inbred BALB C; Nerve Fibers, Unmyelinated; NF-kappa B; Ovalbumin; P-Selectin; Respiratory System; TRPV Cation Channels