RESUMO
Acute gout attacks produce severe joint pain and inflammation associated with monosodium urate (MSU) crystals leading to oxidative stress production. The transient potential receptor ankyrin 1 (TRPA1) is expressed by a subpopulation of peptidergic nociceptors and, via its activation by endogenous reactive oxygen species, including hydrogen peroxide (H2O2), contributes to pain and neurogenic inflammation. The aim of this study was to investigate the role of TRPA1 in hyperalgesia and inflammation in a model of acute gout attack in rodents. Inflammatory parameters and mechanical hyperalgesia were measured in male Wistar rats and in wild-type (Trpa1(+/+)) or TRPA1-deficient (Trpa1(-/-)) male mice. Animals received intra-articular (ia, ankle) injection of MSU. The role of TRPA1 was assessed by receptor antagonism, gene deletion or expression, sensory fiber defunctionalization, and calcitonin gene-related peptide (CGRP) release. We found that nociceptor defunctionalization, TRPA1 antagonist treatment (via ia or oral administration), and Trpa1 gene ablation abated hyperalgesia and inflammatory responses (edema, H2O2 generation, interleukin-1ß release, and neutrophil infiltration) induced by ia MSU injection. In addition, we showed that MSU evoked generation of H2O2 in synovial tissue, which stimulated TRPA1 producing CGRP release and plasma protein extravasation. The MSU-elicited responses were also reduced by the H2O2-detoxifying enzyme catalase and the reducing agent dithiothreitol. TRPA1 activation by MSU challenge-generated H2O2 mediates the entire inflammatory response in an acute gout attack rodent model, thus strengthening the role of the TRPA1 receptor and H2O2 production as potential targets for treatment of acute gout attacks.
Assuntos
Gota/metabolismo , Peróxido de Hidrogênio/metabolismo , Hiperalgesia/metabolismo , Inflamação/metabolismo , Canais de Cátion TRPC/metabolismo , Animais , Antioxidantes/farmacologia , Western Blotting , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND AND PURPOSE: Transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) are involved in many biological processes, including nociception and hyperalgesia. Whereas the involvement of TRPV1 in psychiatric disorders such as anxiety and depression has been reported, little is known regarding the role of TRPA1 in these conditions. EXPERIMENTAL APPROACH: We investigated the role of TRPA1 in mice models of depression [forced swimming test (FST)] and anxiety [elevated plus maze (EPM) test]. KEY RESULTS: Administration of the TRPA1 antagonist (HC030031, 30 nmol in 2 µL, i.c.v.) reduced immobility time in the FST. Similar results were obtained after oral administration of HC030031 (30-300 mg·kg(-1) ). The reduction in immobility time in FST induced by HC030031 (100 mg·kg(-1) ) was completely prevented by pretreatment with TRPA1 agonist, cinnamaldehyde (50 mg·kg(-1) , p.o.), which per se was inactive. In the EPM test, pretreatment with cinnamaldehyde (50 mg·kg(-1) , p.o.), which per se did not affect behaviour response, prevented the anxiolytic-like effect (increased open arm exploration) evoked by TRPA1 blockade (HC030031, 100 mg·kg(-1) , p.o.). Treatment with either cinnamaldehyde or HC030031 did not affect spontaneous ambulation. Furthermore, TRPA1-deficient mice showed anxiolytic- and antidepressant-like phenotypes in the FST and EPM test respectively. CONCLUSION AND IMPLICATIONS: The present findings indicate that genetic deletion or pharmacological blockade of TRPA1 produces inhibitory activity in mouse models of anxiety and depression. These results imply that TRPA1 exerts tonic control, promoting anxiety and depression, and that TRPA1 antagonism has potential as an innovative strategy for the treatment of anxiety and mood disorders.