ABSTRACT
Contact dermatitis is a very common inflammatory reaction in the skin, causing not only aesthetic problems but also loss functionality at work. The molecular mechanisms of contact dermatitis induced by chemical irritants are still unclear. Considering that transient receptor potential channels (TRP) may induce neurogenic inflammation and the exacerbation of inflammatory responses, here we investigated the role of transient receptor potential channel ankyrin type-1 (TRPA1) in skin inflammation evoked by chemical irritants. Ear oedema and nociceptive responses elicited by the topical application of xylene and toluene were measured in Swiss mice, wild type and TRPA1 knockout (Trpa1-/-) C57BL/6 mice. Histological analyses were performed in mice subjected to the ear oedema assay. Topical application of xylene and toluene in the mouse ear induced an edematogenic response (0.113⯱â¯0.008â¯mm and 0.067⯱â¯0.011â¯mm), compared to vehicle (0.008⯱â¯0.008â¯mm), assessed by ear thickness measurements and histological analyses. These responses were prevented by topical pretreatment with a selective TRPA1 antagonist, HC-030031 (% inhibition: xylene 36.8⯱â¯9.4% and toluene 50.7⯱â¯11.0%), and by the genetic deletion of TRPA1 ((% inhibition: xylene 66.6⯱â¯16.7% and toluene 75⯱â¯0%). In addition, the topical application of xylene and toluene to the mouse paw elicited nociceptive responses, which were significantly reduced by oral treatment with HC-030031 ((% of inhibition: 84.9⯱â¯1.3% and 27.1⯱â¯8.0%, respectively); nociceptive responses were almost completely abolished in Trpa1-/-mice. Our data suggest that the activation of TRPA1 could be involved in some of the symptoms of irritant-mediated contact dermatitis, such as oedema, pain and neurogenic inflammation.
Subject(s)
Skin/drug effects , TRPA1 Cation Channel/metabolism , Toluene/pharmacology , Xylenes/pharmacology , Animals , Edema/chemically induced , Edema/genetics , Edema/metabolism , Edema/pathology , Gene Knockout Techniques , Inflammation/chemically induced , Inflammation/metabolism , Mice , Mice, Inbred C57BL , Nociception/drug effects , TRPA1 Cation Channel/antagonists & inhibitors , TRPA1 Cation Channel/deficiency , TRPA1 Cation Channel/genetics , VolatilizationABSTRACT
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.
