Cannabinoid Agonists Inhibit Neuropathic Pain Induced by Brachial Plexus Avulsion in Mice by Affecting Glial Cells and MAP Kinases

Many studies have shown the antinociceptive effects of cannabinoid (CB) agonists in different models of pain. Herein, we have investigated their relevance in neuropathic pain induced by brachial plexus avulsion (BPA) in mice.Mice underwent BPA or sham surgery. The mRNA levels and protein expression of CB(1) and CB(2) receptors were assessed by RT-PCR and immunohistochemistry, respectively. The activation of glial cells, MAP kinases and transcription factors were evaluated by immunohistochemistry. The antinociceptive properties induced by cannabinoid agonists were assessed on the 5(th) and 30(th) days after surgery. We observed a marked increase in CB(1) and CB(2) receptor mRNA and protein expression in the spinal cord and dorsal root ganglion, either at the 5(th) or 30(th) day after surgery. BPA also induced a marked activation of p38 and JNK MAP kinases (on the 30(th) day), glial cells, such as microglia and astrocytes, and the transcription factors CREB and NF-κB (at the 5(th) and 30(th) days) in the spinal cord. Systemic treatment with cannabinoid agonists reduced mechanical allodynia on both the 5(th) and 30(th) days after surgery, but the greatest results were observed by using central routes of administration, especially at the 30(th) day. Treatment with WIN 55,212-2 prevented the activation of both glial cells and MAP kinases, associated with an enhancement of CREB and NF-κB activation.Our results indicate a relevant role for cannabinoid agonists in BPA, reinforcing their potential therapeutic relevance for the management of chronic pain states

Evidence for the role of neurogenic inflammation components in trypsin-elicited scratching behaviour in mice

Background and purpose: We investigated the mechanisms underlying the pruritogenic response induced by trypsin in mice, to assess the relevance of neurogenic inflammation components in this response.Experimental approach: 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.Key results: 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 B(2) (FR173657) and B(1) (SSR240612) receptor antagonists. Moreover, an essential role for the mediators of neurogenic inflammation was established, as the selective NK(1)(FK888), NK(3) (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.Conclusions and implications: 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.Univ Fed Santa Catarina, Dept Pharmacol, Ctr Biol Sci, BR-88049900 Florianopolis, SC, BrazilUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilKings Coll London, Div Cardiovasc, London WC2R 2LS, EnglandUniversidade Federal de São Paulo, Dept Biophys, São Paulo, BrazilWeb of Scienc