TRPA1 receptor stimulation by hydrogen peroxide is critical to trigger hyperalgesia and inflammation in a model of acute gout

Abstract

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-1β 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.

Oxidized Phospholipid OxPAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice

“…TRPA1 is also a target of endogenous oxidative products such as 4-hydroxynonenal (4-HNE) and H 2 O 2 that activate TRPA1 directly [3,4]. TRPA1 is a major transducing pathway by which oxidative stress produces acute nociception, allodynia, and hyperalgesia [5,6]. Activation of TRPA1 further produces neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP) which mediate neurogenic inflammatory responses [2].…”

“…The levels of reactive oxygen species contributing to the formation of OxPAPC are highly elevated in inflammatory pain conditions [2,6,19]. However, it remains unknown whether OxPAPC contributes to inflammatory pain.…”

Transient Receptor Potential Ankyrin 1 Enhances Ovalbumin-Induced Acute Allergic Inflammation in Murine Models

“…For example, inflammatory edema caused by TRPA1 activation is dependent on classical inflammatory mechanisms such as mast cell degranulation, neutrophil migration, the release of histamine, serotonin, and adrenalin, and the production of prostaglandins [6, 36]. Activation of TRPA1 has also been shown to enhance the expression of some inflammatory genes such as the prostaglandin-producing enzyme COX-2, myeloperoxidase, IL-6, and IL-1β [6, 9, 10, 21, 37, 38]. …”

Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors

“…H 2 O 2 induces asthma when inhaled 20 and emesis when ingested by activating vagal afferent sensory fibers. 28 H 2 O 2 may also contribute to nociceptive behaviors in animal models of acute joint pain, 29,30 and ischemia-reperfusion injury. 31 In previous studies by others, hindpaw injections of H 2 O 2 produced only brief nociceptive responses, and specific subcutaneous versus deep muscle tissue injections were not characterized.…”