Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1

Materazzi, Serena; Nassini, Romina; André, Eunice; Campi, Barbara; Amadesi, Silvia; Trevisani, Marcello; Bunnett, Nigel W.; Patacchini, Riccardo; Geppetti, Pierangelo

doi:10.1073/pnas.0802354105

Cited by 145 publications

(119 citation statements)

References 51 publications

(78 reference statements)

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“…The transient potential receptor ankyrin 1 (TRPA1) is a nonselective cation channel, coexpressed with TRP vanilloid 1 (TRPV1) in a subset of C-fiber nociceptors, where it functions as a multimodal sensor to noxious stimuli (11,12). TRPA1 shows a unique sensitivity for an unprecedented number of endogenous reactive molecules produced at sites of tissue injury or inflammation, which include ROS, RNS, and RCS (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Novel Therapeutic Strategy to Prevent Chemotherapy-Induced Persistent Sensory Neuropathy By TRPA1 Blockade

et al. 2013

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Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and painful adverse reaction of cancer treatment in patients that is little understood or treated. Cytotoxic drugs that cause CIPN exert their effects by increasing oxidative stress, which activates the ion channel TRPA1 expressed by nociceptors. In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Bortezomib evoked a prolonged mechanical, cold, and selective chemical hypersensitivity (the latter against the TRPA1 agonist allyl isothiocyanate). This CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger a-lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyl-lysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or a-lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Our findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress byproducts in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists. Cancer Res; 73(10); 3120-31. Ó2013 AACR.

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Section: Introductionmentioning

confidence: 99%

Novel Therapeutic Strategy to Prevent Chemotherapy-Induced Persistent Sensory Neuropathy By TRPA1 Blockade

et al. 2013

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“…Mechanical pain sensation also seems to involve TRPA1 activation . Agonists of TRPA1 have been found in the components in natural plants, environmental irradiants and inflammatory compounds (Macpherson et al, 2007;McNamara et al, 2007;Materazzi et al, 2008;Taylor-Clark et al, 2008). For example, isothiocyanates (the pungent component in horseradish and wasabi), allicin (a component of garlic), cinnamaldehyde (an active compound in cinnamon oil), tetrahydrocannabinol (the psychoactive compound in marijuana), acetaldehyde (an ethanol metabolite), 4-hydroxy-2-nonenal (HNE) and prostaglandin J2 (an inflammatory mediator containing reactive α, β -unsaturated aldehydes), which elicit acute pain or neurogenic inflammation by activating TRPA1 expressed in the sensory neurons (Story et al, 2003;Bandell et al, 2004;Jordt et al, 2004;Bautista et al, 2005;Macpherson et al, 2005;Trevisani et al, 2007;Andersson et al, 2008;Andrè et al, 2008;Taylor-Clark et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Gabapentin Attenuates the Activation of Transient Receptor Potential A1 by Cinnamaldehyde

2009

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Gabapentin is used as an effective drug for relieving pain, but the main mechanism is still unclear. Recently, voltage-gated Ca 2＋ channel subunits are suggested for the main target for the analgesic action of gabapentin. We wonder whether gabapentin directly modulates other specific ion channels peripherally expressed in the sensory neurons. To test this, we used a heterologous expression system in which the cell lines transiently expressed thermosensitive transient receptor potential ion channels (thermoTRPs) as well as the primary cultured mouse trigeminal neurons. The application of gabapentin reduced the increases in the intracellular Ca 2＋ level caused by TRPA1 activation in the heterologous expression system whereas the responses via actions of other thermoTRPs were not dramatically affected by the gabapentin treatment. Gabapentin also attenuated the TRPA1-mediated intracellular Ca 2＋ increases in the cultured trigeminal neurons. These findings suggest TRPA1 in the peripheral sensory neurons as a novel target for the analgesic of gabapentin.

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“…Compelling evidence indicates that TRPA1 is gated by an unprecedented series of endogenous agents generated at sites of inflammation and tissue injury. The product of fatty acid metabolism, 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ 2 ), which is synthesized by cyclooxygenases after an initial inflammatory signal, is a potent activator of TRPA1 [136,137]. The cyclopentenone isoprostane 8-iso-PGA2 is also capable of targeting TRPA1 [137].…”

Section: Trpa1mentioning

confidence: 99%

“…The product of fatty acid metabolism, 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ 2 ), which is synthesized by cyclooxygenases after an initial inflammatory signal, is a potent activator of TRPA1 [136,137]. The cyclopentenone isoprostane 8-iso-PGA2 is also capable of targeting TRPA1 [137]. Oxidative decomposition of polyunsaturated fatty acids, such as linoleic and arachidonic acid, leads to the formation of a host of reactive carbonyl species that may target TRPA1.…”

Section: Trpa1mentioning

confidence: 99%

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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Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1

Cited by 145 publications

References 51 publications

Novel Therapeutic Strategy to Prevent Chemotherapy-Induced Persistent Sensory Neuropathy By TRPA1 Blockade

Novel Therapeutic Strategy to Prevent Chemotherapy-Induced Persistent Sensory Neuropathy By TRPA1 Blockade

Gabapentin Attenuates the Activation of Transient Receptor Potential A1 by Cinnamaldehyde

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

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