Is TRPA1 Burning Down TRPV1 as Druggable Target for the Treatment of Chronic Pain?

Giorgi, Simona; Nikolaeva-Koleva, Magdalena; Alarcón-Alarcón, David; Butrón, Laura; González-Rodríguez, Sara

doi:10.3390/ijms20122906

Cited by 38 publications

(30 citation statements)

References 196 publications

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“…Translation of TRPA1 antagonists from pre-clinical to clinical results remains challenging, some have shown strong activity in humans with reduced or no antagonist activity in mice or rats. Additionally, as TRPA1 is expressed in a wide variety of tissues with varying roles in inflammation, this makes it difficult to determine safety and efficacy without very targeted approaches (233,234). Current preclinical models lack tissue specificity for in vivo modeling.…”

Section: Trpa1mentioning

confidence: 99%

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation

et al. 2020

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Transient receptor potential (TRP) channels are a superfamily of non-selective cation channels that act as polymodal sensors in many tissues throughout mammalian organisms. In the context of ion channels, they are unique for their broad diversity of activation mechanisms and their cation selectivity. TRP channels are involved in a diverse range of physiological processes including chemical sensing, nociception, and mediating cytokine release. They also play an important role in the regulation of inflammation through sensory function and the release of neuropeptides. In this review, we discuss the functional contribution of a subset of TRP channels (TRPV1, TRPV4, TRPM3, TRPM8, and TRPA1) that are involved in the body's immune responses, particularly in relation to inflammation. We focus on these five TRP channels because, in addition to being expressed in many somatic cell types, these channels are also expressed on peripheral ganglia and nerves that innervate visceral organs and tissues throughout the body. Activation of these neural TRP channels enables crosstalk between neurons, immune cells, and epithelial cells to regulate a wide range of inflammatory actions. TRP channels act either through direct effects on cation levels or through indirect modulation of intracellular pathways to trigger pro-or antiinflammatory mechanisms, depending on the inflammatory disease context. The expression of TRP channels on both neural and immune cells has made them an attractive drug target in diseases involving inflammation. Future work in this domain will likely yield important new pathways and therapies for the treatment of a broad range of disorders including colitis, dermatitis, sepsis, asthma, and pain.

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Section: Trpa1mentioning

confidence: 99%

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation

et al. 2020

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“…Aside from pain, other diseases could benefit from TRPA1 inhibition [184]. However, similar to TRPV1, TRPA1 has been known for so long that the progress towards a usable analgesic is somewhat disappointing [185].…”

Section: Trp Channelsmentioning

confidence: 99%

Novel Analgesics with Peripheral Targets

Ciotu

Fischer

2020

Neurotherapeutics

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A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.

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“…Recently special focus has been directed towards the Transient Receptor Potential Vanilloid 1 (TRPV1, “capsaicin receptor”) and Ankyrin 1 (TRPA1) ion channels located and often co-expressed mainly on these sensory fibers, which are identified as novel anti-inflammatory, analgesic and gastroprotective targets. These polymodal nociceptors play an important role in thermo-, mechanical- and chemo-sensation, as well as neurogenic inflammation and hyperalgesia [ 9 , 10 , 11 , 12 ]. Besides the exogenous agents, especially spices, like capsaicin (the pungent agent of chili pepper), cinnamaldehyde, allyl isothiocyanate (mustard oil) and allicin, they are activated by several endogenous agents as lipoxygenase products, bradykinin, and protons produced in the inflammatory tissues [ 10 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the TRPA1 Ion Channel in the Gastric Mucosa after Iodoacetamide-Induced Gastritis in Rats: A Potential New Therapeutic Target

Csekő

Pécsi

Kajtár

et al. 2020

IJMS

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Acute gastritis is often untreatable by acid secretion-inhibiting drugs. Understanding the protective mechanisms including the role of Transient Receptor Potential Ankyrin1 (TRPA1) and Vanilloid1 (TRPV1) channels localized on capsaicin-sensitive afferents and non-neuronal structures might identify novel therapeutic approaches. Therefore, we characterized a translational gastritis model using iodoacetamide (IAA) and investigated TRPA1/V1 expressions. Wistar rats and CD1, C57Bl/6J mice were exposed to IAA-containing (0.05, 0.1, 0.2, 0.3, 0.5%) drinking water for 7 or 14 days. Body weight and water consumption were recorded daily. Macroscopic lesions were scored, qualitative histopathologic investigation was performed, TRPA1/V1 immunopositivity and mRNA expressions were measured. IAA induced a concentration-dependent weight loss and reduced water intake in both species. Hyperemia, submucosal edema, inflammatory infiltration and hemorrhagic erosions developed after 7 days, while ulcers after 14 days in rats. Trpa1 mRNA/protein expressions were upregulated at both timepoints. Meanwhile, TRPV1 immunopositivity was upregulated in the gastric corpus after 0.05% IAA ingestion, but downregulated after 0.2%, whereas Trpv1 mRNA did not change. Interestingly, no macroscopic/microscopic changes were observed in mice. These are the first data for the concentration- and duration-dependent changes in the IAA-induced gastritis in rats accompanied by TRPA1 upregulation, therefore, its therapeutic potential in gastritis should further be investigated.

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Is TRPA1 Burning Down TRPV1 as Druggable Target for the Treatment of Chronic Pain?

Cited by 38 publications

References 196 publications

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation

Novel Analgesics with Peripheral Targets

Upregulation of the TRPA1 Ion Channel in the Gastric Mucosa after Iodoacetamide-Induced Gastritis in Rats: A Potential New Therapeutic Target

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