Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain

Yi, Danhui; Wang, Shenglan; Tominaga, Makoto; Yamamoto, Satoshi; Fukuoka, Tetsuo; Higashi, Tomohiro; Kobayashi, Kimiko; Obata, Koichi; Yamanaka, Hiroki; Noguchi, Koichi

doi:10.1172/jci30951c1

Cited by 119 publications

(193 citation statements)

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“…Similar mechanisms of TRPA1 sensitization have been reported to occur by PAR 2 agonists, probably by activation of PLC, which releases the inhibition of TRPA1 from plasma membrane PIP 2 [144]. This evidence suggests that TRPA1 functions as an integrator of different inflammatory mediators, in turn leading to amplification of inflammatory and nociceptive signals.…”

Section: Trpa1supporting

confidence: 75%

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

Nassini¹,

Benemei²,

Fusi³

et al. 2013

TOPAINJ

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Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side effect of many chemotherapeutic drugs, including platinum-based compounds (e.g., cisplatin and oxaliplatin), taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vincristine), and the first-in-class proteasome inhibitor, bortezomib. Among the various sensory symptoms of CIPN, paresthesia, dysesthesia, spontaneous pain, and mechanical and thermal hypersensitivity are prominent. Inflammation, oxidative stress, loss of intraepidermal nerve fibers, modifications of mitochondria, and various ion channels alterations are part of the several mechanisms contributing to CIPN. Because attempts to mitigate chemotherapeutic-induced acute neuronal hyperexcitability and the subsequent peripheral neuropathy have yielded unsatisfactory results, a more in-depth understanding of the mechanism(s) responsible for the neurotoxic action of anticancer drugs is required.Some members of the transient receptor potential (TRP) family of channels, as the TRPV1 and TRPV4 (vanilloid), TRPA1 (ankyrin) and TRPM8 (melastatin) are expressed on the plasma membrane of primary sensory neurons (nociceptors), where they are activated by an unprecedented series of physical and chemical stimuli. There is evidence that TRPV1, TRPV4, TRPA1 and TRPM8 are prominent contributors of mechanical and thermal hypersensitivity in models of CIPN. In particular, in vitro and in vivo studies have pointed out the unique role of TRPA1 and oxidative stress in the mechanism responsible for cold and mechanical hyperalgesia in rodent models of CIPN.

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Section: Trpa1supporting

confidence: 75%

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

Nassini¹,

Benemei²,

Fusi³

et al. 2013

TOPAINJ

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“…Liberated enzymes (e.g., kallikreins) and blood cells (e.g., platelets, mast cells) further contribute to the accumulation of inflammatory mediators and neurogenic inflammation (110,111). A large variety of substances feed back onto nociceptors innervating the injured region and sensitize peripheral terminals by direct and indirect actions at ion channels, receptors, and second messenger cascades (87,102,111,112). The mechanisms by which inflammatory mediators recruit "silent" C-M i H i fibers by endowing these fibers with prolonged mechanical and heat sensitivity (25,60) is unknown but may involve long-lasting alterations in second messenger signaling cascades and sensitization of nocisensors.…”

Section: Adaptive and Maladaptive Shifts In Pain Thresholdmentioning

confidence: 99%

“…The mechanisms by which inflammatory mediators recruit "silent" C-M i H i fibers by endowing these fibers with prolonged mechanical and heat sensitivity (25,60) is unknown but may involve long-lasting alterations in second messenger signaling cascades and sensitization of nocisensors. Decreased thermal and chemical thresholds in the primary area are due in part to sensitization of TRPV1 and TRPA1 by numerous components of the "inflammatory soup" including BK (36,(85)(86)(87)112). Although TRPV1 is not the only transducer of acute noxious heat, it is the major contributor to the development of heat hyperalgesia, perhaps due to its expression in polymodal neurons capable of inducing neurogenic inflammation and modifying central connections (42,43).…”

Section: Adaptive and Maladaptive Shifts In Pain Thresholdmentioning

confidence: 99%

Nociceptors: the sensors of the pain pathway

Dubin

Patapoutian²

2010

J. Clin. Invest.

1,026

856

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Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals, and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. The activation of functionally distinct cutaneous nociceptor populations and the processing of information they convey provide a rich diversity of pain qualities. Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics.

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“…Studies on the interactions of PARs and channels such as the TRP family could be the challenges and opportunities of future research in molecular mechanism of PARs-regulated inflammatory pain. PAR 2 is also co-expressed with other members of the TRP family in sensory neurons such as TRPV4 [65,66] and TRPA1 [67,68]. In sensory neurons, PAR 2 activation potentiates the response of those cells to agonists of TRPA1 [68] or TRPV4 [66].…”

Section: Interaction Of Protease-activated Receptors With Transient Rmentioning

confidence: 99%

“…PAR 2 is also co-expressed with other members of the TRP family in sensory neurons such as TRPV4 [65,66] and TRPA1 [67,68]. In sensory neurons, PAR 2 activation potentiates the response of those cells to agonists of TRPA1 [68] or TRPV4 [66]. Moreover, TRPV4 potentiation was also dependent on histamine and serotonin receptors activation [69].…”

Section: Interaction Of Protease-activated Receptors With Transient Rmentioning

confidence: 99%

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Cenac

2013

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Abstract:The protease-activated receptors (PARs) play a pivotal role in inflammatory and nociceptive processes. PARs have raised considerable interest because of their capacity to regulate numerous aspects of viscera physiology and pathophysiology. The present article summarizes research on PARs and proteases as signalling molecules in visceral pain. In particular, experiments in animal models suggest that PAR 2 is important for visceral hypersensitivity. Moreover, endogenous PAR 2 agonists seem to be released by colonic tissue of patients suffering from irritable bowel syndrome, suggesting a role for this receptor in visceral pain perception. Thus, PARs, together with proteases that activate them, represent exciting targets for therapeutic intervention on visceral pain.

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Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain

Cited by 119 publications

References 0 publications

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

Nociceptors: the sensors of the pain pathway

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

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