Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1


The vanilloid receptor-1 (VR1) is a heat-gated ion channel that is responsible for the burning sensation elicited by capsaicin. A similar sensation is reported by patients with esophagitis when they consume alcoholic beverages or are administered alcohol by injection as a medical treatment. We report here that ethanol activates primary sensory neurons, resulting in neuropeptide release or plasma extravasation in the esophagus, spinal cord or skin. Sensory neurons from trigeminal or dorsal root ganglia as well as VR1-expressing HEK293 cells responded to ethanol in a concentration-dependent and capsazepine-sensitive fashion. Ethanol potentiated the response of VR1 to capsaicin, protons and heat and lowered the threshold for heat activation of VR1 from 42°C to 34°C. This provides a likely mechanistic explanation for the ethanol-induced sensory responses that occur at body temperature and for the sensitivity of inflamed tissues to ethanol, such as might be found in esophagitis, neuralgia or wounds.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Ethanol-induced neurotransmitter release and plasma extravasation.
Figure 2: Ethanol stimulates and potentiates native and recombinant VR1 responses.
Figure 3: Ethanol modulates capsaicin-, anandamide- or proton-gated inward currents recorded from hVR1-expressing HEK293 cells.
Figure 4: Ethanol shifts the threshold for VR1 heat activation.


  1. Fardy, M.J. & Patton, D.W. Complications associated with peripheral alcohol injections in the management of trigeminal neuralgia. Br. J. Oral Maxillofac. Surg. 32, 387–391 (1994).

    Article  CAS  Google Scholar 

  2. Caterina, M.J. et al. The capsaicin receptor: a heat activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    Article  CAS  Google Scholar 

  3. Hayes, P. et al. Cloning and functional expression of a human orthologue of rat vanilloid receptor-1. Pain 88, 205–215 (2000).

    Article  CAS  Google Scholar 

  4. Tominaga, M. et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531–543 (1998).

    Article  CAS  Google Scholar 

  5. Zygmunt, P.M. et al. Vanilloid receptors on sensory nerves mediate the vasodillator action of anandamide. Nature 400, 452–457 (1999).

    Article  CAS  Google Scholar 

  6. Smart, D. et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J. Pharmacol. 129, 227–230 (2000).

    Article  CAS  Google Scholar 

  7. Hwang, S.W. et al. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc. Natl. Acad. Sci. USA 97, 6155–6160 (2000).

    Article  CAS  Google Scholar 

  8. Holzer, P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol. Rev. 43, 143–201 (1991).

    CAS  PubMed  Google Scholar 

  9. Bevan, S. et al. Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br. J. Pharmacol. 107, 544–552 (1992).

    Article  CAS  Google Scholar 

  10. Docherty, R.J., Yates, J.C. & Piper, A.S. Capsazepine block of voltage-activated calcium channels in adult rat dorsal root ganglion neurones in culture. Br. J. Pharmacol. 121, 1461–1467 (1997).

    Article  CAS  Google Scholar 

  11. Saria, A. et al. Vascular protein leakage in various tissues induced by substance P, capsaicin, bradykinin, serotonin, histamine and antigen challenge. Naunyn Schmiedebergs Arch. Pharmacol. 324, 212–218 (1983).

    Article  CAS  Google Scholar 

  12. Forman, S.A. & Zhou, Q. Novel modulation of a nicotinic receptor channel mutant reveals that the open state is stabilized by ethanol. Mol. Pharmacol. 55, 102–108 (1999).

    Article  CAS  Google Scholar 

  13. Wick, M.J. et al. Mutations of γ-aminobutyric acid and glycine receptors change alcohol cutoff: evidence for an alcohol receptor? Proc. Natl. Acad. Sci. USA 95, 6504–6509 (1998).

    Article  CAS  Google Scholar 

  14. Stubbs, C.D. & Slater, S.J. Ethanol and protein kinase C. Alcohol Clin. Exp. Res. 23, 1552–1560 (1999).

    Article  CAS  Google Scholar 

  15. Premkumar, L.S. & Ahern, G.P. Induction of vanilloid receptor channel activity by protein kinase C. Nature 408, 985–990 (2000).

    Article  CAS  Google Scholar 

  16. Cesare, P. & McNaughton, P. A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin. Proc. Natl. Acad. Sci. USA 93, 15435–15439 (1996).

    Article  CAS  Google Scholar 

  17. Nagy, I. & Rang, H.P. Similarities and differences between the responses of rat sensory neurons to noxious heat and capsaicin. J. Neurosci. 19, 10647–10655 (1999).

    Article  CAS  Google Scholar 

  18. Bolanowski, S.J., Gescheider, G.A. & Sutton, S.V. Relationship between oral pain and ethanol concentration in mouthrinses. J. Periodontal. Res. 30, 192–197 (1995).

    Article  CAS  Google Scholar 

  19. Liang, Y.-F., Haake, B. & Reeh, P.W. Sustained sensitization and recruitment of rat cutaneous nociceptors by bradykinin and a novel theory of its excitatory action. J. Physiol. 532, 229–239 (2001).

    Article  CAS  Google Scholar 

  20. Caterina, M.J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000).

    Article  CAS  Google Scholar 

  21. Davis, J.B. et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405, 183–187 (2000).

    Article  CAS  Google Scholar 

  22. Yiangou, Y. et al. Vanilloid receptor 1 immunoreactivity in inflamed bowel. Lancet 357, 1338–1339 (2001).

    Article  CAS  Google Scholar 

  23. Smid, S.D. et al. Oesophagitis-induced changes in capsaicin-sensitive tachykininergic pathways in the ferret lower oesophageal sphincter. Neurogastroenterol. Motil. 10, 403–411 (1998).

    Article  CAS  Google Scholar 

  24. Tognetto, M. et al. Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 (VR-1) activation. J. Neurosci. 15, 1104–1109 (2001).

    Article  Google Scholar 

Download references


We thank C. Farrant and S. Lomax for preparation of artwork. This work was supported in part by ARCA (Padua) and Cofin (MIUIR, Rome).

Author information

Authors and Affiliations


Corresponding author

Correspondence to J B. Davis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Trevisani, M., Smart, D., Gunthorpe, M. et al. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5, 546–551 (2002).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing