Abstract
Acupuncture is an invasive procedure commonly used to relieve pain. Acupuncture is practiced worldwide, despite difficulties in reconciling its principles with evidence-based medicine. We found that adenosine, a neuromodulator with anti-nociceptive properties, was released during acupuncture in mice and that its anti-nociceptive actions required adenosine A1 receptor expression. Direct injection of an adenosine A1 receptor agonist replicated the analgesic effect of acupuncture. Inhibition of enzymes involved in adenosine degradation potentiated the acupuncture-elicited increase in adenosine, as well as its anti-nociceptive effect. These observations indicate that adenosine mediates the effects of acupuncture and that interfering with adenosine metabolism may prolong the clinical benefit of acupuncture.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
NIH Consensus Conference. Acupuncture. J. Am. Med. Assoc. 280, 1518–1524 (1998).
Culliton, B.J. Acupuncture: fertile ground for faddists and serious NIH research. Science 177, 592–594 (1972).
Bonafede, M., Dick, A., Noyes, K., Klein, J.D. & Brown, T. The effect of acupuncture utilization on healthcare utilization. Med. Care 46, 41–48 (2008).
Zhao, Z.Q. Neural mechanism underlying acupuncture analgesia. Prog. Neurobiol. 85, 355–375 (2008).
Han, J.S. Acupuncture and endorphins. Neurosci. Lett. 361, 258–261 (2004).
Huang, C., Wang, Y., Han, J.S. & Wan, Y. Characteristics of electroacupuncture-induced analgesia in mice: variation with strain, frequency, intensity and opioid involvement. Brain Res. 945, 20–25 (2002).
Lao, L. et al. A parametric study of electroacupuncture on persistent hyperalgesia and Fos protein expression in rats. Brain Res. 1020, 18–29 (2004).
Li, W.M. et al. Analgesic effect of electroacupuncture on complete Freund's adjuvant–induced inflammatory pain in mice: a model of antipain treatment by acupuncture in mice. Jpn. J. Physiol. 55, 339–344 (2005).
Abbracchio, M.P., Burnstock, G., Verkhratsky, A. & Zimmermann, H. Purinergic signaling in the nervous system: an overview. Trends Neurosci. 32, 19–29 (2009).
Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev. 87, 659–797 (2007).
Sjölund, K.F., Segerdahl, M. & Sollevi, A. Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain. Anesth. Analg. 88, 605–610 (1999).
Maione, S. et al. The antinociceptive effect of 2-chloro-2′-C-methyl-N6-cyclopentyladenosine (2′-Me-CCPA), a highly selective adenosine A1 receptor agonist, in the rat. Pain 131, 281–292 (2007).
Sawynok, J., Reid, A. & Poon, A. Peripheral antinociceptive effect of an adenosine kinase inhibitor, with augmentation by an adenosine deaminase inhibitor, in the rat formalin test. Pain 74, 75–81 (1998).
Cui, M., Tang, X., Christian, W.V., Yoon, Y. & Tieu, K. Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the Mitochondrial Division Inhibitor mdivi-1. J. Biol. Chem. 285, 11740–11752 (2010).
Volonté, M.G., Yuln, G., Quiroga, P. & Consolini, A.E. Development of an HPLC method for determination of metabolic compounds in myocardial tissue. J. Pharm. Biomed. Anal. 35, 647–653 (2004).
Li, J., King, N.C. & Sinoway, L.I. Interstitial ATP and norepinephrine concentrations in active muscle. Circulation 111, 2748–2751 (2005).
Li, J., King, N.C. & Sinoway, L.I. ATP concentrations and muscle tension increase linearly with muscle contraction. J. Appl. Physiol. 95, 577–583 (2003).
Bekar, L. et al. Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor. Nat. Med. 14, 75–80 (2008).
Lohse, M.J. et al. 2-Chloro-N6-cyclopentyladenosine: a highly selective agonist at A1 adenosine receptors. Naunyn Schmiedebergs Arch. Pharmacol. 337, 687–689 (1988).
Raghavendra, V., Tanga, F.Y. & DeLeo, J.A. Complete Freunds adjuvant–induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur. J. Neurosci. 20, 467–473 (2004).
Sun, D. et al. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc. Natl. Acad. Sci. USA 98, 9983–9988 (2001).
Vadakkan, K.I., Jia, Y.H. & Zhuo, M. A behavioral model of neuropathic pain induced by ligation of the common peroneal nerve in mice. J. Pain 6, 747–756 (2005).
Wei, F. & Zhuo, M. Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetized rat. J. Physiol. (Lond.) 532, 823–833 (2001).
Davis, K.D., Taylor, S.J., Crawley, A.P., Wood, M.L. & Mikulis, D.J. Functional MRI of pain- and attention-related activations in the human cingulate cortex. J. Neurophysiol. 77, 3370–3380 (1997).
Karlsten, R., Gordh, T. & Post, C. Local antinociceptive and hyperalgesic effects in the formalin test after peripheral administration of adenosine analogues in mice. Pharmacol. Toxicol. 70, 434–438 (1992).
Reeve, A.J. & Dickenson, A.H. Electrophysiological study on spinal antinociceptive interactions between adenosine and morphine in the dorsal horn of the rat. Neurosci. Lett. 194, 81–84 (1995).
Burnstock, G. Acupuncture: a novel hypothesis for the involvement of purinergic signaling. Med. Hypotheses 73, 470–472 (2009).
Fredholm, B.B., IJzerman, A.P., Jacobson, K.A., Klotz, K.N. & Linden, J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 53, 527–552 (2001).
Chen, J.F. et al. A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J. Neurosci. 19, 9192–9200 (1999).
Poortmans, J. Principles of Exercise Biochemistry (Karger, Brussels, 2003).
Quintero, I.B. et al. Prostatic acid phosphatase is not a prostate-specific target. Cancer Res. 67, 6549–6554 (2007).
Zylka, M.J. et al. Prostatic acid phosphatase is an ectonucleotidase and suppresses pain by generating adenosine. Neuron 60, 111–122 (2008).
Cunha, R.A. & Sebastiao, A.M. Extracellular metabolism of adenine nucleotides and adenosine in the innervated skeletal muscle of the frog. Eur. J. Pharmacol. 197, 83–92 (1991).
Golembiowska, K., White, T.D. & Sawynok, J. Modulation of adenosine release from rat spinal cord by adenosine deaminase and adenosine kinase inhibitors. Brain Res. 699, 315–320 (1995).
Lamanna, N. & Kay, N.E. Pentostatin treatment combinations in chronic lymphocytic leukemia. Clin. Adv. Hematol. Oncol. 7, 386–392 (2009).
Fredholm, B.B. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 14, 1315–1323 (2007).
Sawynok, J. Adenosine receptor activation and nociception. Eur. J. Pharmacol. 347, 1–11 (1998).
Eisenach, J.C. et al. Intrathecal but not intravenous opioids release adenosine from the spinal cord. J. Pain 5, 64–68 (2004).
Takakura, N. & Yajima, H. Analgesic effect of acupuncture needle penetration: a double-blind crossover study. Open Med. 3, e54–61 (2009).
Weidenhammer, W., Linde, K., Streng, A., Hoppe, A. & Melchart, D. Acupuncture for chronic low back pain in routine care: a multicenter observational study. Clin. J. Pain 23, 128–135 (2007).
Kelly, R.B. Acupuncture for pain. Am. Fam. Physician 80, 481–484 (2009).
Salter, M.W. & Henry, J.L. Evidence that adenosine mediates the depression of spinal dorsal horn neurons induced by peripheral vibration in the cat. Neuroscience 22, 631–650 (1987).
Sichardt, K. & Nieber, K. Adenosine A(1) receptor: functional receptor-receptor interactions in the brain. Purinergic Signal. 3, 285–298 (2007).
Zijlstra, F.J., van den Berg-de Lange, I., Huygen, F.J. & Klein, J. Anti-inflammatory actions of acupuncture. Mediators Inflamm. 12, 59–69 (2003).
Castrop, H. et al. Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73-deficient mice. J. Clin. Invest. 114, 634–642 (2004).
Martucci, C. et al. The purinergic antagonist PPADS reduces pain related behaviors and interleukin-1 beta, interleukin-6, iNOS and nNOS overproduction in central and peripheral nervous system after peripheral neuropathy in mice. Pain 137, 81–95 (2008).
Acknowledgements
This work was supported by a grant from the US National Institutes of Health to M.N. and K.T.
Author information
Authors and Affiliations
Contributions
All authors contributed to experimental design and execution and manuscript preparation.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6 (PDF 978 kb)
Rights and permissions
About this article
Cite this article
Goldman, N., Chen, M., Fujita, T. et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci 13, 883–888 (2010). https://doi.org/10.1038/nn.2562
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2562
This article is cited by
-
Electroacupuncture Alleviates Pain by Suppressing P2Y12R-Dependent Microglial Activation in Monoarthritic Rats
Neurochemical Research (2024)
-
Effect of perioperative acupoint electrical stimulation on macrophages in mice under operative stress
Journal of Inflammation (2023)
-
Electroacupuncture Exerts Analgesic Effects by Restoring Hyperactivity via Cannabinoid Type 1 Receptors in the Anterior Cingulate Cortex in Chronic Inflammatory Pain
Molecular Neurobiology (2023)
-
Wissenschaftliche Mängel im CME-Artikel zur Komplementärmedizin in der Schmerztherapie
Der Schmerz (2023)
-
The real-time detection of acupuncture-induced extracellular ATP mobilization in acupoints and exploration of its role in acupuncture analgesia
Purinergic Signalling (2023)