Transient receptor potential channels: targeting pain at the source

Patapoutian, Ardem; Tate, Simon; Woolf, Clifford J.

doi:10.1038/nrd2757

Cited by 569 publications

(541 citation statements)

References 161 publications

(211 reference statements)

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“…Whether TRPM8-mediated analgesia is dependent on peripheral and/or central sites of action is unknown but may be addressed now that TRPM8-expressing neurons and their peripheral and central fibers can be visualized by GFP expression driven by the TRPM8 promoter (76,77). Importantly, studies in humans and mice reveal species differences in pathways sensing innocuous cold: A-fiber block completely suppresses the cold response in humans (78), yet the majority of TRPM8-expressing fibers responsible for innocuous cold transduction in mice have small diameters (76,77) Noxious cold stimuli activate NSC currents and calcium influx (10,79) and decrease K + channel activity (80) and Na + /K + -ATPase function (65) ( Table 3). The temporal dissociation of the qualities of pain/ache vs. prickle/heat to noxious cold (3°C) suggest underlying differences in transduction mechanisms or information processing (66).…”

Section: Transduction Of Noxious Coldmentioning

confidence: 99%

Nociceptors: the sensors of the pain pathway

Dubin

Patapoutian²

2010

J. Clin. Invest.

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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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Section: Transduction Of Noxious Coldmentioning

confidence: 99%

Nociceptors: the sensors of the pain pathway

Dubin

Patapoutian²

2010

J. Clin. Invest.

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1,071

856

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“…Upregulation of TRP channels has been claimed as a possible mechanism for protracted sensory neuropathy, but this phenomenon has not been always demonstrated. It is highly possible that additional molecular mechanisms are involved in TRP hyperactivity, including altered intracellular transduction pathways and/or epigenetic factors, which have been previously proposed to play a key role in models of inflammatory and neuropathic pain [69,83,155]. Thus, further studies are required to identify the upstream and downstream events concerning the primary sensory neurons, which are associated to chemotherapeutic agent-evoked and TRPmediated hypersensitivity, and ultimately to CIPN.…”

Section: Resultsmentioning

confidence: 99%

“…The mechanism through which oxaliplatin/cisplatininduced neuropathy results in TRPV1 sensitization is unclear. However, enhanced TRPV1 protein trafficking, consequent upon mRNA overexpression, to peripheral nerve processes, or channel phosphorylation by different kinases, leading to enhanced TRPV1 sensitivity, have been proposed as a general mechanism contributing to pathological pain states [83].…”

Section: Trpv1mentioning

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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“…TRPV1 ion channels have important functions as cellular sensors, and are involved in nociception, taste perception, thermosensation, mechano‐ and osmolarity sensing, and regulation of signal transmission 15, 55, 56. In addition to ECS and physicochemical activators,15, 33, 55, 56, 57, 58 TRPV1 is activated by tetrahydrocannabinol, cannabinol, cannabigerol and some propyl homologs of THC and cannabigerol 59, 60, 61, 62, 63, 64, 65, 66, 67. Cannabichromene (CBC), cannabidiol, and cannabinol are strong TRPA1 agonists and desensitizers, and THCV (from a botanical extract) is a potent regulator of TRPA1 62…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%