sb-366791 and Neurogenic-Inflammation

Transient receptor potential vanilloid (TRPV1) receptors are abundant in a subpopulation of primary sensory neurons that convey nociceptive information from the periphery to the spinal cord dorsal horn. The TRPV1 receptors are expressed on both the peripheral and central branches of these dorsal root ganglion (DRG) neurons and can be activated by capsaicin, heat, low pH, and also by recently described endogenous lipids. Using patch-clamp recordings from superficial dorsal horn (DH) neurons in acute spinal cord slices, the effect of application of the endogenous TRPV1 agonist N-oleoyldopamine (OLDA) on the frequency of miniature excitatory postsynaptic currents (mEPSCs) was evaluated. A high concentration OLDA (10 microM) solution was needed to increase the mEPSC frequency, whereas low concentration OLDA (0.2 microM) did not evoke any change under control conditions. The increase was blocked by the TRPV1 antagonists SB366791 or BCTC. Application of a low concentration of OLDA evoked an increase in mEPSC frequency after activation of protein kinase C by phorbol ester (PMA) and bradykinin or in slices from animals with peripheral inflammation. Increasing the bath temperature from 24 to 34 degrees C enhanced the basal mEPSC frequency, but the magnitude of changes in the mEPSC frequency induced by OLDA administration was similar at both temperatures. Our results suggest that presumed endogenous agonists of TRPV1 receptors, like OLDA, could have a considerable impact on synaptic transmission in the spinal cord, especially when TRPV1 receptors are sensitized. Spinal TRPV1 receptors could play a pivotal role in modulation of nociceptive signaling in inflammatory pain.

Topics: Analysis of Variance; Anilides; Animals; Animals, Newborn; Bradykinin; Cinnamates; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Excitatory Postsynaptic Potentials; Ganglia, Spinal; In Vitro Techniques; Male; Neurogenic Inflammation; Pain Measurement; Patch-Clamp Techniques; Phorbol Esters; Rats; Rats, Wistar; Sensory Receptor Cells; Signal Transduction; Spinal Cord; Temperature; TRPV Cation Channels; Vasodilator Agents

We investigated the mechanisms underlying the pruritogenic response induced by trypsin in mice, to assess the relevance of neurogenic inflammation components in this response.. Itching was induced by an intradermal injection of trypsin in the mouse neck. The animals were observed for 40 min and their scratching behaviour was quantified.. Trypsin-induced itching was blocked by the lima bean trypsin inhibitor, the selective proteinase-activated receptor-2 (PAR-2) antagonist FSLLRY and PAR-2 receptor desensitization. An important involvement of mast cells was observed, as chronic pretreatment with the mast cell degranulator compound 48/80 or the mast cell stabilizer disodium cromoglycate prevented scratching. Also, trypsin response was inhibited by the selective COX-2 inhibitor celecoxib and by the selective kinin B2 (FR173657) and B1 (SSR240612) receptor antagonists. Moreover, an essential role for the mediators of neurogenic inflammation was established, as the selective NK1 (FK888), NK3 (SR142801) and calcitonin gene-related peptide (CGRP(8-37) fragment) receptor antagonists inhibited trypsin-induced itching. Similarly, blockade of transient receptor potential vanilloid 1 (TRPV1) receptors by the selective TRPV1 receptor antagonist SB366791, or by genetic deletion of TRPV1 receptor reduced this behaviour in mice. C-fibre desensitization showed a very similar result.. Trypsin intradermal injection proved to be a reproducible model for the study of itching and the involvement of PAR-2 receptors. Also, trypsin-induced itching seems to be widely dependent on neurogenic inflammation, with a role for TRPV1 receptors. In addition, several other mediators located in the sensory nerves and skin also seem to contribute to this process.

Topics: Anilides; Animals; Antipruritics; Behavior, Animal; Bradykinin Receptor Antagonists; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Celecoxib; Cell Degranulation; Cinnamates; Cromolyn Sodium; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dioxoles; Disease Models, Animal; Injections, Intradermal; Male; Mast Cells; Mice; Mice, Knockout; Nerve Fibers, Unmyelinated; Neurogenic Inflammation; Oligopeptides; p-Methoxy-N-methylphenethylamine; Peptide Fragments; Plant Proteins; Pruritus; Pyrazoles; Quinolines; Receptor, PAR-2; Receptors, Bradykinin; Receptors, Calcitonin Gene-Related Peptide; Reproducibility of Results; Signal Transduction; Sulfonamides; TRPV Cation Channels; Trypsin