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  • Review Article
  • Published:

Transient receptor potential channels: targeting pain at the source

Nature Reviews Drug Discovery volume 8, pages 55–68 (2009)Cite this article

Key Points

  • The 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.

Abstract

Pain results from the complex processing of neural signals at different levels of the central nervous system, with each signal potentially offering multiple opportunities for pharmacological intervention. A logical strategy for developing novel analgesics is to target the beginning of the pain pathway, and aim potential treatments directly at the nociceptors — the high-threshold primary sensory neurons that detect noxious stimuli. The largest group of receptors that function as noxious stimuli detectors in nociceptors is the transient receptor potential (TRP) channel family. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting drugs, and discusses the development pathways needed to test candidates as analgesics in humans.

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Figure 1: Classification of major pain syndromes.
Figure 2: Representation of the roles of TRP channels in the peripheral and central terminals of nociceptor neurons.
Figure 3: Changes in TRP channels produced by inflammation.
Figure 4: TRP channel antagonists and agonists as analgesics.
Figure 5: TRP drugs currently under development as analgesics.

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Acknowledgements

We thank S. E. Kim for help putting together boxes 2 and 3.

Author information

Authors and Affiliations

  1. The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, ICND210F, 92037, California, USA

    Ardem Patapoutian

  2. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, 92121, California, USA

    Ardem Patapoutian

  3. GlaxoSmithKline Research and Development, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, UK

    Simon Tate

  4. Massachusetts General Hospital and Harvard Medical School, 149 13th Charlestown, Massachusetts, 02129, USA

    Clifford J. Woolf

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Correspondence to Clifford J. Woolf.

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Competing interests

A.P. has received research support from the Genomics Institute of the Novartis Foundation. S.T. is a full-time employee of GlaxoSmithKline. C.J.W. has been a scientific advisor, consultant or received research support from Solace Pharmaceuticals, Hydra Biosciences, Pfizer, GlaxoSmithKline and Abbott.

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DATABASES

IUPHAR Receptor Database

TRPA1

TRPM2

TRPM4

TRPM5

TRPM8

TRPV1

TRPV2

TRPV3

TRPV4

FURTHER INFORMATION

Amgen

Anesiva

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Glenmark

Glenmark GRC15133 and GRC 17173

Glenmark press release

Neurogen

NeurogesX

Pain Genes database

Glossary

Nociceptor

A high-threshold primary sensory neuron that detects or responds to noxious stimuli.

Inflammatory pain

Pain associated with tissue injury and inflammation characterized by reduced threshold and increased responsiveness.

Neuropathic pain

Pain associated with a lesion to the nervous system.

Michael addition reaction

Nucleophilic addition to an alpha or beta unsaturated carbonyl group.

Click reaction

Copper(I)-catalysed azide-alkyne cycloaddition reaction that can be used for in vivo labelling of molecules.

Endocannabinoids

Endogenous agonists of cannabinoid receptors in animals.

Endovanilloid

An endogenous ligand of the TRPV1 receptor.

Peripheral sensitization

Reduction in the threshold for activation of the peripheral terminal of nociceptors produced by inflammatory mediators.

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Patapoutian, A., Tate, S. & Woolf, C. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 8, 55–68 (2009). https://doi.org/10.1038/nrd2757

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