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1.
Allergy ; 69(10): 1424-7, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25041656

ABSTRACT

2,4-Dinitrochlorobenzene (DNCB) is widely used in human clinical studies and in experimental animal studies to evoke allergic contact dermatitis. 2,4-Dinitrochlorobenzene is a potent immunogen capable of inducing contact sensitization in all humans exposed. However, the mechanism by which DNCB evokes such symptoms is presently unknown. TRPA1 is a nonselective cation channel that is expressed in peptidergic sensory neurons and fibroblasts. TRPA1 activation was recently implicated in the pathophysiology of atopic dermatitis especially in transducing cutaneous itch signals. Here, we test the hypothesis that DNCB acts as a TRPA1 agonist and thereby evokes allergic symptoms. We found that DNCB activates human TRPA1 dose dependently in FLIPR experiments with an EC50 of 167 nM, an effect that was fully blocked by selective TRPA1 antagonists Chembridge-5861528 and A-967079. Similarly, DNCB activated nonselective TRPA1 current in patch clamp studies. Neutralization of 3 critical cysteines in TRPA1 resulted in a loss of DNCB agonism.


Subject(s)
Dermatitis, Allergic Contact/immunology , Dinitrochlorobenzene/immunology , Irritants/immunology , Nerve Tissue Proteins/agonists , Transient Receptor Potential Channels/agonists , Calcium Channels , HEK293 Cells , Humans , Patch-Clamp Techniques , TRPA1 Cation Channel
2.
J Physiol Pharmacol ; 64(3): 331-40, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23959730

ABSTRACT

We characterized pain behavior and cutaneous blood flow response induced by activation of the spinal transient receptor potential ankyrin 1 (TRPA1) channel using intrathecal drug administrations in the rat. Additionally, we assessed whether the pronociceptive actions induced by intrathecally administered dynorphin A, cholecystokinin or prostaglandin F(2α) are mediated by the spinal TRPA1 channel. Cinnamaldehyde, a TRPA1 agonist, produced a dose-related (3-10 µg) cutaneous blood flow increase and mechanical hypersensitivity effect. These effects at the currently used doses were of short duration and attenuated, although not completely, by pretreatment with A-967079, a TRPA1 antagonist. The cinnamaldehyde-induced hypersensitivity was also reduced by pretreatment with minocycline (an inhibitor of microglial activation), but not by carbenoxolone (a gap junction decoupler). In vitro study, however, indicated that minocycline only poorly blocks the TRPA1 channel. The mechanical hypersensitivity effect induced by dynorphin A, but not that by cholecystokinin or prostaglandin F(2α), was attenuated by a TRPA1 antagonist Chembridge-5861528 as well as A-967079. The cinnamaldehyde-induced cutaneous blood flow increase was not suppressed by MK-801, an NMDA receptor antagonist, or bicuculline, a GABA(A) receptor antagonist. The results indicate that spinal TRPA1 channels promote mechanical pain hypersensitivity and due to antidromic activation of nociceptive nerve fibers increase cutaneous blood flow. The attenuation of the cinnamaldehyde-induced hypersensitivity effect by minocycline may be explained by action other than block of the TRPA1 channel. Moreover, the spinal TRPA1 channel is involved in mediating the pronociceptive action of dynorphin A, but not that of the spinal cholecystokinin or prostaglandin F(2α).


Subject(s)
Analgesics, Non-Narcotic/therapeutic use , Back Pain/drug therapy , Dynorphins/antagonists & inhibitors , Hyperalgesia/drug therapy , Posterior Horn Cells/drug effects , Skin/drug effects , TRPC Cation Channels/antagonists & inhibitors , Acrolein/administration & dosage , Acrolein/adverse effects , Acrolein/analogs & derivatives , Acrolein/antagonists & inhibitors , Analgesics, Non-Narcotic/administration & dosage , Animals , Back Pain/etiology , Back Pain/metabolism , Behavior, Animal/drug effects , Cholecystokinin/administration & dosage , Cholecystokinin/antagonists & inhibitors , Cholecystokinin/metabolism , Dinoprost/administration & dosage , Dinoprost/antagonists & inhibitors , Dinoprost/metabolism , Dose-Response Relationship, Drug , Dynorphins/administration & dosage , Dynorphins/metabolism , Hyperalgesia/chemically induced , Hyperalgesia/metabolism , Injections, Spinal , Male , Minocycline/administration & dosage , Minocycline/therapeutic use , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/metabolism , Oximes/administration & dosage , Oximes/therapeutic use , Physical Stimulation/adverse effects , Posterior Horn Cells/metabolism , Rats , Rats, Wistar , Regional Blood Flow/drug effects , Skin/blood supply , TRPA1 Cation Channel , TRPC Cation Channels/agonists , TRPC Cation Channels/metabolism
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