Transient receptor potential ankyrin 1 receptor stimulation by hydrogen peroxide is critical to trigger pain during monosodium urate-induced inflammation in rodents.

Published on Nov 1, 2013in Arthritis & Rheumatism9.586
路 DOI :10.1002/ART.38112
Gabriela Trevisan28
Estimated H-index: 28
(UFSM: Universidade Federal de Santa Maria),
Carin Hoffmeister11
Estimated H-index: 11
(UFSM: Universidade Federal de Santa Maria)
+ 9 AuthorsJuliano Ferreira54
Estimated H-index: 54
(UFSC: Universidade Federal de Santa Catarina)
Sources
Abstract
Objective Gout is a common cause of inflammatory arthritis and is provoked by the accumulation of monosodium urate (MSU) crystals. However, the underlying mechanisms of the pain associated with acute attacks of gout are poorly understood. The aim of this study was to evaluate the role of transient receptor potential ankyrin 1 (TRPA-1) and TRPA-1 stimulants, such as H2O2, in a rodent model of MSU-induced inflammation. Methods MSU or H2O2 was injected into the hind paws of rodents or applied in cultured sensory neurons, and the intracellular calcium response was measured in vitro. Inflammatory or nociceptive responses in vivo were evaluated using pharmacologic, genetic, or biochemical tools and methods. Results TRPA-1 antagonism, TRPA-1 gene deletion, or pretreatment of peptidergic TRP-expressing primary sensory neurons with capsaicin markedly decreased MSU-induced nociception and edema. In addition to these neurogenic effects, MSU increased H2O2 levels in the injected tissue, an effect that was abolished by the H2O2-detoxifying enzyme catalase. H2O2, but not MSU, directly stimulated sensory neurons through the activation of TRPA-1. The nociceptive responses evoked by MSU or H2O2 injection were attenuated by the reducing agent dithiothreitol. In addition, MSU injection increased the expression of TRPA-1 and TRP vanilloid channel 1 (TRPV-1) and also enhanced cellular infiltration and interleukin-1尾 levels, and these effects were blocked by TRPA-1 antagonism. Conclusion Our results suggest that MSU injection increases tissue H2O2, thereby stimulating TRPA-1 on sensory nerve endings to produce inflammation and nociception. TRPV-1, by a previously unknown mechanism, also contributes to these responses.
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References48
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#1Kenneth L. Rock (UMMS: University of Massachusetts Medical School)H-Index: 96
#2Hiroshi Kataoka (UMMS: University of Massachusetts Medical School)H-Index: 16
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Uric acid not only triggers inflammation in gout in its crystallized form, monosodium urate, but is also associated with comorbidities of the disease. New insights into the role of uric acid as a danger signal for both adaptive and innate immune responses could help to explain the pathogenesis of gout and point to potential new avenues of therapy for this and other sterile inflammatory diseases.
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#1Noriyuki Hatano (Aichi Gakuin University)H-Index: 15
#2Yuka Itoh (Aichi Gakuin University)H-Index: 15
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Abstract Transient receptor potential ankyrin repeat 1 (TRPA1) forms calcium (Ca2+)- and zinc (Zn2+)- permeable ion channels that sense noxious substances. Despite of biological and clinical importance of TRPA1, there is little knowledge of the mechanisms that lead to transcriptional regulation of TRPA1 and of the functional role of transcriptionally induced-TRPA1. Here we show induction of TRPA1 by inflammatory mediators and delineate the underlying molecular mechanisms and functional relevance...
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#1Elizabeth S. Fernandes ('KCL': King's College London)H-Index: 30
#2M. A. Fernandes ('KCL': King's College London)H-Index: 2
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The transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) channels are members of the TRP superfamily of structurally related, non-selective cation channels. It is rapidly becoming clear that the functions of TRPV1 and TRPA1 interlink with each other to a considerable extent. This is especially clear in relation to pain and neurogenic inflammation where TRPV1 is coexpressed on the vast majority of TRPA1-expressing sensory nerves and both integrate a variety of no...
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#1Edin茅ia L. Andrade (UFSC: Universidade Federal de Santa Catarina)H-Index: 15
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Abstract The necessity of safe and effective treatments for chronic pain has intensified the search for new analgesic drugs. In the last few years, members of a closely-related family of ion channels, called transient receptor potential (TRP) have been identified in different cell types and their functions in physiological and pathological conditions have been characterized. The transient receptor potential ankyrin 1 (TRPA1), originally called ANKTM1 (ankyrin-like with transmembrane domains prot...
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Abstract Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED 50 [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value]聽=聽0.04 [95% confidence interval 0.01鈥0.11]聽mg/paw) and edema (ED 50 =聽0.08 [95% confidence interval 0.04鈥...
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Transient receptor potential (TRP) channels have been extensively studied over the past years. Yet, in most cases, the gating mechanisms of these polymodal cation channels still remain a puzzle. Using the nociceptive channel TRPA1 as an example, we discuss the role of dynamic regulation of the pore size (pore dilatation) on channel gating. Additionally, we critically revise current knowledge of the role of intracellular domains, such as ankyrin repeats and EF hand motifs, in channel activation a...
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