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The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept

Nature Reviews Drug Discovery volume 6, pages 357–372 (2007)Cite this article

A Corrigendum to this article was published on 01 June 2007

Key Points

  • The vanilloid receptor TRPV1 (transient receptor potential vanilloid subfamily, member 1) is now recognized as a molecular integrator of noxious stimuli ranging from pungent natural products (for example, capsaicin and resiniferatoxin), acidic environment and noxious heat to putative 'endovanilloids' (that is, endogenous TRPV1 agonists). Protons and endovanilloids in an inflammatory soup act together to reduce the thermal-activation threshold of TRPV1. In addition, TRPV1 is modulated through phosphorylation by kinases and is released by phospholipase C from the inhibitory control of PIP2 (phosphatidylinositol 4,5-bisphosphate).

  • TRPV1 is expressed in primary sensory neurons where it appears to be upregulated in various human disease states, including inflammatory bowel disease, irritable bowel syndrome, vulvodynia and mastalgia.

  • TRPV1 is unique in that its excitation by agonists is followed by a lasting refractory state, traditionally referred to as desensitization. Combined, the above findings identify TRPV1 as an attractive target for novel analgesic and anti-inflammatory drugs. Indeed, capsaicin has been in clinical use to relieve chronic neuropathic and inflammatory pain and to suppress urinary bladder overactivity.

  • The clinical use of TRPV1 antagonists is based on the concept that endovanilloids acting on TRPV1 might provide a major contribution to certain pain conditions. The ability of small-molecule TRPV1 antagonists to ameliorate symptoms in animal models of chronic pain, inclusive of cancer pain, proves that this concept works.

  • Several small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine.

  • We argue that TRPV1 agonists and antagonists are not mutually exclusive but rather complementary therapeutic approaches for pain relief. TRPV1 modulators alone or in conjunction with other analgesics are expected to improve the quality of life of people with migraine or chronic intractable pain secondary to cancer, AIDS or diabetes.

  • TRPV1 is also expressed in the CNS and in non-neuronal tissues, where the functions of this receptor are only beginning to be understood. Clearly, TRPV1 is more than a pain sensor. Emerging data indicate that TRPV1 modulators may also be useful in treating disorders other than pain such as urinary urge incontinence, chronic cough, diabetes and irritable bowel syndrome.

Abstract

The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine. Moreover, animal models suggest a therapeutic value for TRPV1 antagonists in the treatment of other types of pain, including pain from cancer. We argue that TRPV1 antagonists alone or in conjunction with other analgesics will improve the quality of life of people with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes. Moreover, emerging data indicate that TRPV1 antagonists could also be useful in treating disorders other than pain, such as urinary urge incontinence, chronic cough and irritable bowel syndrome. The lack of effective drugs for treating many of these conditions highlights the need for further investigation into the therapeutic potential of TRPV1 antagonists.

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Figure 1: Schematic summary of TRPV1 signal integration in the peripheral nociceptor terminal.
Figure 2: Chemical structures of selected TRPV1 ligands.
Figure 3: Activation of thermoTRPs by naturally occurring compounds.
Figure 4: Key binding interactions of TRPV1 antagonists.

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Acknowledgements

A PubMed search using the keyword TRPV1 identified 582 references. We apologize to the authors whose work could not be cited here owing to space limitations. We are grateful to S. Kane, J. Van Adelsberg, R. Blanchard, B. Chenard and J. E. Krause for their critical reading of the manuscript. We would also like to thank A. Eid for providing most of the photographs used in Figure 3 and F. and K. Starr (www.hear.org/starr) for the photograph of camphor.

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Authors and Affiliations

  1. Department of Pathology, Monmouth Medical Center, Long Branch, New Jersey 07740 and Drexel University College of Medicine, Philadelphia, USA

    Arpad Szallasi

  2. Department of Biochemistry and Molecular Biology, Neurogen Corporation, Branford, 06405, Connecticut, USA

    Daniel N. Cortright

  3. Department of Chemistry, Neurogen Corporation, Branford

    Charles A. Blum

  4. Department of Pain Research, Merck Research Laboratories, West Point, Philadelphia, USA

    Samer R. Eid

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  1. Arpad Szallasi
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Correspondence to Arpad Szallasi.

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Competing interests

D.N.C., C.A.B. and S..R.E. are employed by commercial entities that are developing TRPV1 antagonists for the treatment of pain and other conditions.

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Szallasi, A., Cortright, D., Blum, C. et al. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6, 357–372 (2007). https://doi.org/10.1038/nrd2280

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