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.

Dopamine mediates vagal modulation of the immune system by electroacupuncture


Previous anti-inflammatory strategies against sepsis, a leading cause of death in hospitals, had limited efficacy in clinical trials, in part because they targeted single cytokines and the experimental models failed to mimic clinical settings1,2,3. Neuronal networks represent physiological mechanisms, selected by evolution to control inflammation, that can be exploited for the treatment of inflammatory and infectious disorders3. Here, we report that sciatic nerve activation with electroacupuncture controls systemic inflammation and rescues mice from polymicrobial peritonitis. Electroacupuncture at the sciatic nerve controls systemic inflammation by inducing vagal activation of aromatic L-amino acid decarboxylase, leading to the production of dopamine in the adrenal medulla. Experimental models with adrenolectomized mice mimic clinical adrenal insufficiency4, increase the susceptibility to sepsis and prevent the anti-inflammatory effects of electroacupuncture. Dopamine inhibits cytokine production via dopamine type 1 (D1) receptors. D1 receptor agonists suppress systemic inflammation and rescue mice with adrenal insufficiency from polymicrobial peritonitis. Our results suggest a new anti-inflammatory mechanism mediated by the sciatic and vagus nerves that modulates the production of catecholamines in the adrenal glands. From a pharmacological perspective, the effects of selective dopamine agonists mimic the anti-inflammatory effects of electroacupuncture and can provide therapeutic advantages to control inflammation in infectious and inflammatory disorders.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Electroacupuncture controls systemic inflammation in sepsis via the sciatic and vagus nerves and catecholamines from the adrenal glands.
Figure 2: Electroacupuncture induces the expression of DOPA decarboxylase and dopamine.
Figure 3: Electroacupuncture rescues mice from established polymicrobial peritonitis.
Figure 4: D1 receptor agonist rescues mice from established polymicrobial peritonitis with adrenal insufficiency.


  1. Angus, D.C. & van der Poll, T. Severe sepsis and septic shock. N. Engl. J. Med. 369, 840–851 (2013).

    Article  CAS  Google Scholar 

  2. Ulloa, L. & Tracey, K.J. The “cytokine profile”: a code for sepsis. Trends Mol. Med. 11, 56–63 (2005).

    Article  CAS  Google Scholar 

  3. Ulloa, L. The vagus nerve and the nicotinic anti-inflammatory pathway. Nat. Rev. Drug Discov. 4, 673–684 (2005).

    Article  CAS  Google Scholar 

  4. Annane, D. Adrenal insufficiency in sepsis. Curr. Pharm. Des. 14, 1882–1886 (2008).

    Article  CAS  Google Scholar 

  5. Tracey, K.J. et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330, 662–664 (1987).

    Article  CAS  Google Scholar 

  6. Riedemann, N.C., Guo, R.F. & Ward, P.A. Novel strategies for the treatment of sepsis. Nat. Med. 9, 517–524 (2003).

    Article  CAS  Google Scholar 

  7. Ulloa, L., Brunner, M., Ramos, L. & Deitch, E.A. Scientific and clinical challenges in sepsis. Curr. Pharm. Des. 15, 1918–1935 (2009).

    Article  CAS  Google Scholar 

  8. Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002).

    Article  CAS  Google Scholar 

  9. Abraham, E. et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit. Care Med. 29, 503–510 (2001).

    Article  CAS  Google Scholar 

  10. Borovikova, L.V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to LPS. Nature 405, 458–462 (2000).

    Article  CAS  Google Scholar 

  11. Huston, J.M. et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med. 203, 1623–1628 (2006).

    Article  CAS  Google Scholar 

  12. Peña, G. et al. Cholinergic regulatory lymphocytes re-establish neuromodulation of innate immune responses in sepsis. J. Immunol. 187, 718–725 (2011).

    Article  Google Scholar 

  13. Bernik, T.R. et al. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. J. Vasc. Surg. 36, 1231–1236 (2002).

    Article  Google Scholar 

  14. Altavilla, D. et al. Activation of the cholinergic anti-inflammatory pathway reduces NF-kappab activation, blunts TNF-α production, and protects againts splanchic artery occlusion shock. Shock 25, 500–506 (2006).

    Article  CAS  Google Scholar 

  15. Cai, B. et al. α7 cholinergic-agonist prevents systemic inflammation and improves survival during resuscitation. J. Cell. Mol. Med. 13, 3774–3785 (2009).

    Article  Google Scholar 

  16. van Westerloo, D.J. et al. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 130, 1822–1830 (2006).

    Article  CAS  Google Scholar 

  17. Pullan, R.D. et al. Transdermal nicotine for active ulcerative colitis. N. Engl. J. Med. 330, 811–815 (1994).

    Article  CAS  Google Scholar 

  18. Wang, H. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat. Med. 10, 1216–1221 (2004).

    Article  CAS  Google Scholar 

  19. van Westerloo, D.J. et al. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J. Infect. Dis. 191, 2138–2148 (2005).

    Article  CAS  Google Scholar 

  20. Vickers, A.J. et al. Acupuncture for chronic pain: individual patient data meta-analysis. Arch. Intern. Med. 172, 1444–1453 (2012).

    Article  Google Scholar 

  21. Lee, A. & Done, M.L. Stimulation of the wrist acupuncture point P6 for preventing postoperative nausea and vomiting. Cochrane Database Syst. Rev. CD003281 (2004).

  22. Napadow, V. & Kaptchuk, T.J. Patient characteristics for outpatient acupuncture in Beijing, China. J. Altern. Complement. Med. 10, 565–572 (2004).

    Article  Google Scholar 

  23. Wu, H.M. et al. Acupuncture for stroke rehabilitation. Cochrane Database Syst. Rev. CD004131 (2006).

  24. Goldman, N. et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat. Neurosci. 13, 883–888 (2010).

    Article  CAS  Google Scholar 

  25. Ernst, E., Lee, M.S. & Choi, T.Y. Acupuncture: does it alleviate pain and are there serious risks? A review of reviews. Pain 152, 755–764 (2011).

    Article  CAS  Google Scholar 

  26. Vida, G. et al. β2-Adrenoreceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system. FASEB J. 25, 4476–4485 (2011).

    Article  CAS  Google Scholar 

  27. Coupland, R.E., Parker, T.L., Kesse, W.K. & Mohamed, A.A. The innervation of the adrenal gland. III. Vagal innervation. J. Anat. 163, 173–181 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).

    Article  CAS  Google Scholar 

  29. Vida, G., Peña, G., Deitch, E.A. & Ulloa, L. α7-nicotinic receptor mediates vagal induction of splenic norepinephrine. J. Immunol. 186, 4340–4346 (2011).

    Article  CAS  Google Scholar 

  30. Grenader, A. & Healy, D.P. Fenoldopam is a partial agonist at dopamine-1 (DA1) receptors in LLC-PK1 cells. J. Pharmacol. Exp. Ther. 258, 193–198 (1991).

    CAS  PubMed  Google Scholar 

  31. Weber, R.R. et al. Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1-receptor agonist, in hypertensive patients. Br. J. Clin. Pharmacol. 25, 17–21 (1988).

    Article  CAS  Google Scholar 

  32. Denef, C., Manet, D. & Dewals, R. Dopaminergic stimulation of prolactin release. Nature 285, 243–246 (1980).

    Article  CAS  Google Scholar 

  33. Gorissen, H. & Laduron, P. Solubilisation of high-affinity dopamine receptors. Nature 279, 72–74 (1979).

    Article  CAS  Google Scholar 

  34. Morelli, A. et al. Prophylactic fenoldopam for renal protection in sepsis: a randomized, double-blind, placebo-controlled pilot trial. Crit. Care Med. 33, 2451–2456 (2005).

    Article  CAS  Google Scholar 

  35. Sorkin, L.S. & Yaksh, T.L. Behavioral models of pain states evoked by physical injury to the peripheral nerve. Neurotherapeutics 6, 609–619 (2009).

    Article  Google Scholar 

  36. Richner, M., Bjerrum, O.J., Nykjaer, A. & Vaegter, C.B. The spared nerve injury (SNI) model of induced mechanical allodynia in mice. J. Vis. Exp. 3092 (2011).

  37. Kadl, A., Pontiller, J., Exner, M. & Leitinger, N. Single bolus injection of bilirubin improves the clinical outcome in a mouse model of endotoxemia. Shock 28, 582–588 (2007).

    CAS  PubMed  Google Scholar 

  38. Panayotis, N. et al. Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse. Neurobiol. Dis. 41, 385–397 (2011).

    Article  CAS  Google Scholar 

  39. Ulloa, L., Doody, J. & Massague, J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397, 710–713 (1999).

    Article  CAS  Google Scholar 

Download references


We thank P. Morcillo, J.M. Inclan-Rico and J.R. Berlin for their comments and suggestions and M. Marks (University of Colorado) and B. Kobilka (Stanford University) for the α7nAChR and β2AR knockout mice. R.T.-R. was supported by the University Autónoma Benito Juarez de Oaxaca. M.d.R.T.-B. was supported by the Mexican National Council for Science and Technology. L.U. is supported by the faculty program of the Department of Surgery of the New Jersey Medical School, the Foundation of University of Medicine and Dentistry of New Jersey and US National Institutes of Health grant RO1-GM084125.

Author information

Authors and Affiliations



R.T.-R., G.Y., G.P., P.M. and M.d.R.T.-B. performed the experiments, prepared the figures and revised the article. M.A.M.-E., L.A.A.-P. and A.I. contributed to the design of the study and revised the paper. L.U. designed and directed the study and wrote the paper.

Corresponding author

Correspondence to Luis Ulloa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 199 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Torres-Rosas, R., Yehia, G., Peña, G. et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med 20, 291–295 (2014).

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