Transient receptor potential channels: targeting pain at the source View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-01

AUTHORS

Ardem Patapoutian, Simon Tate, Clifford J. Woolf

ABSTRACT

Key PointsThe detection of noxious stimuli by nociceptors is mediated by high-threshold transducers expressed on their peripheral terminal membranes. These transducers are receptor/ion channels that convert thermal, mechanical and chemical stimuli into ion fluxes that excite the neuron to produce a sensory inflow.Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins and encode thermal and chemical stimuli.Among the TRP channels expressed by nociceptors, TRPV1 and TRPA1 have been the most extensively investigated, and represent validated targets for the development of novel analgesics.In addition to detecting noxious stimuli, the density, threshold and kinetics of TRPV1 and TRPA1 are modulated by inflammatory mediators, and in this way sensitize nociceptors to increase pain sensitivity after tissue damage or on exposure to inflammation.TRPV1 and TRPA1 are also expressed on the central terminals of sensory neurons where they seem to act as synaptic modulators. Antagonists acting at these two channels are promising candidates as analgesics by virtue of blocking the activation of the channels in response to noxious stimuli or inflammation.TRP nociceptive transducer proteins may have adaptive actions beyond simply detecting noxious stimuli, including body temperature control, synaptic plasticity, and respiratory and cardiovascular function, which may produce adverse effects when blocked.TRP channel agonists can also produce analgesia by either desensitizing the receptors or, at high doses, ablating them.TRP channels can be used as a drug delivery system to target small cationic drugs selectively into nociceptors.Overall, targeting nociceptive TRP channels, where the pain-pathway begins, represents a promising opportunity for the development of novel analgesics. More... »

PAGES

55-68

References to SciGraph publications

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  • 2007-08-16. Derivation and comparison of C57BL/6 embryonic stem cells to a widely used 129 embryonic stem cell line in TRANSGENIC RESEARCH
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  • 2007-01-28. Direct activation of the ion channel TRPA1 by Ca2+ in NATURE NEUROSCIENCE
  • 2001-06. The trp ion channel family in NATURE REVIEWS NEUROSCIENCE
  • 2007-10. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers in NATURE
  • 2005-12-14. Heat activation of TRPM5 underlies thermal sensitivity of sweet taste in NATURE
  • 2006-09-24. Nitric oxide activates TRP channels by cysteine S-nitrosylation in NATURE CHEMICAL BIOLOGY
  • 2005-04-24. PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain in NATURE NEUROSCIENCE
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    http://scigraph.springernature.com/pub.10.1038/nrd2757

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    DIMENSIONS

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    PUBMED

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    44 schema:description Key PointsThe detection of noxious stimuli by nociceptors is mediated by high-threshold transducers expressed on their peripheral terminal membranes. These transducers are receptor/ion channels that convert thermal, mechanical and chemical stimuli into ion fluxes that excite the neuron to produce a sensory inflow.Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins and encode thermal and chemical stimuli.Among the TRP channels expressed by nociceptors, TRPV1 and TRPA1 have been the most extensively investigated, and represent validated targets for the development of novel analgesics.In addition to detecting noxious stimuli, the density, threshold and kinetics of TRPV1 and TRPA1 are modulated by inflammatory mediators, and in this way sensitize nociceptors to increase pain sensitivity after tissue damage or on exposure to inflammation.TRPV1 and TRPA1 are also expressed on the central terminals of sensory neurons where they seem to act as synaptic modulators. Antagonists acting at these two channels are promising candidates as analgesics by virtue of blocking the activation of the channels in response to noxious stimuli or inflammation.TRP nociceptive transducer proteins may have adaptive actions beyond simply detecting noxious stimuli, including body temperature control, synaptic plasticity, and respiratory and cardiovascular function, which may produce adverse effects when blocked.TRP channel agonists can also produce analgesia by either desensitizing the receptors or, at high doses, ablating them.TRP channels can be used as a drug delivery system to target small cationic drugs selectively into nociceptors.Overall, targeting nociceptive TRP channels, where the pain-pathway begins, represents a promising opportunity for the development of novel analgesics.
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