Advertisement

Chinese Journal of Integrative Medicine

, Volume 23, Issue 11, pp 812–815 | Cite as

Nitric oxide signaling molecules in acupoints: Toward mechanisms of acupuncture

  • Sheng-xing Ma
Feature Article

Abstract

Recent clinical trial studies have demonstrated that the effects of acupuncture on pain improvement are small and no difference between acupoints and non-points. Whether acupuncture needles must be inserted in specific points depends on whether acupoint specificity exists that is still not resolved, and is now urgent. Previous anatomical studies have demonstrated that acupoints exist higher number of nerve fibers/trunks, blood vessels, hair follicles, and sweat glands as well as density of the gap junction. Recent evidence shows that nitric oxide (NO) level is elevated in the acupoints/ meridians and is associated with an enhanced expression of NO synthase endowed with transient receptor potential vanilloid type-1. There is growing evidence from international groups showing that acupuncture induces NO-mediated vasodilatation, which increases local blood flow and allows for a flush of algesic or sensitizing substances, leading to pain relief. Previous studies, using a novel biocapture system, have demonstrated that NOx (total nitrite and nitrate) and cyclic guanosine monophosphate (cGMP) concentrations are consistently increased over skin acupoints compared to non-meridian control regions (NMCR) in humans. Dermal microdialysis in humans showed that NO-cGMP releases in the subcutaneous tissue of acupoint are higher than those in NMCR and increased by electroacupuncture (EA). Recent studies have demonstrated that low-frequency electrical stimulation and manual acupuncture with low stimulating force and rate produce an elevation of NO release predominantly over acupoints. In contrast, NO levels over the areas of the skin regions are moderately reduced by high-frequency EA stimulation. The results from anatomical and biochemical studies consistently show that acupoints exist higher levels of NO signaling molecules, and stimulus-evoked NO release is also with a higher level at acupoints. Results suggest that NO signaling molecules contribute to the specificity of acupoints, and selecting well-trained acupuncturetists for using correct acupoints and appropriate parameters should improve acupuncture clinical trial studies.

Keywords

acupoint nitric oxide electroacupuncture manual acupuncture reinforcement methods 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Acupuncture. NIH Consensus Statement Online 1997;15:1–34.Google Scholar
  2. 2.
    Yin C, Buchheit TE, Park JJ. Acupuncture for chronic pain: an update and critical overview. Curr Opin Anaesthesiol 2017;30:583–592.CrossRefPubMedGoogle Scholar
  3. 3.
    Ma SX. Neurobiology of acupuncture: Toward CAM. Evid Based Complement Alternat Med 2004;1:41–47.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Chan SH. What is being stimulated in acupuncture: evaluation of the existence of a specific substrate? Neurosci Biobehav Rev 1984;8:25–33.CrossRefPubMedGoogle Scholar
  5. 5.
    Xing JJ, Zeng BY, Li J, Zhuang Y, Liang FR. Acupuncture point specificity. Int Rev Neurobiol 2013;111:49–65.CrossRefPubMedGoogle Scholar
  6. 6.
    Campbell A. Point specificity of acupuncture in the light of recent clinical and imaging studies. Acupunct Med 2006;24:118–122.CrossRefPubMedGoogle Scholar
  7. 7.
    MacPherson H, Maschino AC, Lewith G, Foster NE, Witt CM, Vickers AJ, et al. Characteristics of acupuncture treatment associated with outcome: an individual patient meta-analysis of 17,922 patients with chronic pain in randomised controlled trials. PLoS One 2013;8:e77438.CrossRefGoogle Scholar
  8. 8.
    Manheimer E, White A, Berman B, Forys K, Ernst E. Meta-analysis: Acupuncture for low back pain. Ann Intern Med 2005;142:651–663.CrossRefPubMedGoogle Scholar
  9. 9.
    Vickers AJ, Cronin AM, Maschino AC, Lewith G, MacPherson H, Foster NE, et al. Acupuncture for chronic pain: individual patient data meta-analysis. Arch Intern Med 2012;172:1444–1453.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dunning J, Butts R, Mourad F, Young I, Flannagan S, Perreault T. Dry needling: a literature review with implications for clinical practice guidelines. Phys Ther Rev 2014;19:252–265.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fan AY, Xu J, Li YM. Evidence and expert opinions. Dry needling versus acupuncture (II): The American Alliance for Professional Acupuncture Safety (AAPAS) White Paper 2016. Chin J Integr Med 2017;23:83–90.PubMedGoogle Scholar
  12. 12.
    Beijing College of Traditional Chinese Medicine, Shanghai College of Traditional Chinese Medicine, Nanjing College of Traditional Chinese Medicine The Acupuncture Institute of the Academy of Traditional Chinese Medicine. Essentials of Chinese acupuncture. Beijing: Foreign Languages Press; 1980:301–310.Google Scholar
  13. 13.
    Chan WW, Weissensteiner H, Rausch WD, Chen KY, Wu LS, Lin JH. Comparison of substance P concentration in acupuncture points in different tissues in dogs. Am J Chin Med 1998;XXVI:13–18.CrossRefGoogle Scholar
  14. 14.
    Luciani RJ. Direct observation and photography of electroconductive points on human skin. Am J Acup 1978;6:311–317.Google Scholar
  15. 15.
    Wang ZT, Wu SL, Cao YC, Zhu ZX, Xu RM. Morphological study on the low impedance line along channel. Acup Res 1987;1:82–85.Google Scholar
  16. 16.
    Fan JY, Xi SY, Liu Z, Wei ZM. The role of gap junctions in determing skin conductance and their possible relationship to acupuncture points and meridians. Am J Acup 1990;18:163–170.Google Scholar
  17. 17.
    Zheng JY, Fan JY, Zhang YJ, Guo Y, Xu TP. Further evidence for the role of gap junctions in acupoint information transfer. Am J Acup 1996;24:291–296.Google Scholar
  18. 18.
    Hoffmann A, Gloe T, Pohl U, Zahler S. Nitric oxide enhances de novo formation of endothelial gap junctions. Cardiovasc Res 2003;60:421–430.CrossRefPubMedGoogle Scholar
  19. 19.
    Cayabyab FS, Daniel EE. K+ channel opening mediates hyperpolarizations by nitric oxide donors and IJPs in opossum esophagus. Am J Physiol 1995;268(5 Pt 1):G831–G842.PubMedGoogle Scholar
  20. 20.
    Javid PJ, Watts SW, Webb RC. Inhibition of nitric oxide-induced vasodilation by gap junction inhibitors: a potential role for a cGMPindependent nitric oxide pathway. J Vasc Res 1996;33:395–404.CrossRefPubMedGoogle Scholar
  21. 21.
    Ma SX. Enhanced nitric oxide concentrations and expression of nitric oxide synthase in acupuncture points/meridians. J Alter Comp Med 2003;9:207–215.CrossRefGoogle Scholar
  22. 22.
    Ibrahim TS, Chen ML, Ma SX. TRPV1 expression in acupuncture points: response to electroacupuncture stimulation. J Chem Neuroanat 2011;41:129–136.CrossRefGoogle Scholar
  23. 23.
    Raiszadeh MM, Ross MM, Russo PS, Schaepper MA, Zhou W, Deng J, et al. Proteomic analysis of eccrine sweat: implications for the discovery of schizophrenia biomarker proteins. J Proteome Res 2012;11:2127–2139.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Paunel AN, Dejam A, Thelen S, Kirsch M, Horstjann M, Gharini P, et al. Enzyme-independent nitric oxide formation during UVA challenge of human skin: characterization, molecular sources, and mechanisms. Free Radic Biol Med 2005;38:606–615.CrossRefPubMedGoogle Scholar
  25. 25.
    Weller R, Pattullo S, Smith L, Golden M, Ormerod A, Benjamin N. Nitric oxide is generated on the skin surface by reduction of sweat nitrate. J Invest Dermatol 1996;107:327–331.CrossRefPubMedGoogle Scholar
  26. 26.
    Suschek CV, Schewe T, Sies H, Kröncke KD. Nitrite, a naturally occurring precursor of nitric oxide that acts like a 'prodrug'. Biol Chem 2006;387:499–506.CrossRefPubMedGoogle Scholar
  27. 27.
    Weitzberg E, Lundberg JO. Nonenzymatic nitric oxide production in humans. Nitric Oxide 1998;2:1–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Ignarro LJ, Fukuto JM, Griscavage JM, Rogers NE, Byrns RE. Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: Comparison with enzymatically formed nitric oxide from L-arginine. Proc Natl Acad Sci 1993;90:8103–8107.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ignarro LJ. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 1999;30:535–560.CrossRefGoogle Scholar
  30. 30.
    Ma SX, Ignarro LJ, Byrns R, Li XY. Increased nitric oxide production in posterior hypothalamus and central sympathetic function on arterial pressure tolerance to nitroglycerin in rats. Nitric Oxide: Biol Chem 1999;3:153–161.CrossRefGoogle Scholar
  31. 31.
    Akaike T, Yoshida M, Miyamoto Y, Sato K, Kohno M, Sasamoto K, et al. Antagonist action of imidazolineoxl N-oxides against endothelium-derived relaxing factor/ NO through a radical reaction. Biochemistry 1993;32:827–832.CrossRefPubMedGoogle Scholar
  32. 32.
    Yoshida M, Akaiki T, Wada Y, Sato K, Ikeda K, Ueda S, et al. Therapeutic effects of Imidazolineoxyl N-oxide against endotoxin shock through its direct nitric oxide-scavenging activity. Biochem Biophys Res Commun 1994;202:923–930.CrossRefPubMedGoogle Scholar
  33. 33.
    Ma SX, Li XY, Sakurai T, Pandjaitan M. Evidence of enhanced nonenzymatic nitric oxide generation on the skin surface of acupuncture points: An innovative approach in humans. Nitric Oxide Biol Chem 2007;17:60–68.CrossRefGoogle Scholar
  34. 34.
    Ma SX, Li XY, Smith BT, Lim N. Changes in nitric oxide, cGMP, and nitrotyrosine concentrations over skin along the meridians in obese subjects. Obesity 2011;19:1560–1567.CrossRefPubMedGoogle Scholar
  35. 35.
    Ma SX, Lee P, Li XY, Jiang I, Ma E, Hu J. Influence of age, gender, and race on nitric oxide release over acupuncture points-meridians. Sci Rep 2015;5:17547.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ma SX, Mayer E, Lee P, Li XY, Gao EZ. Transcutaneous electrical nerve stimulation increased nitric oxide-cyclic cGMP release biocaptured over skin surface of the pericardium meridian and acupuncture points in humans. Acup Electro-Therapeutics Res 2015;40:73–86.CrossRefGoogle Scholar
  37. 37.
    Lim N, Ma SX. Responses of nitric oxide-cGMP releases in acupuncture point to electroacupuncture in human skin in vivo using dermal microdialysis. Microcirculation 2009;16:434–443.CrossRefGoogle Scholar
  38. 38.
    Ha Y, Kim M, Nah J, Suh M, Lee Y. Measurements of locationdependent nitric oxide levels on skin surface in relation to acupuncture point. Evid Based Complement Alternat Med 2012;2012:781460.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kimura K, Takeuchi H, Yuri K, Wakayama I. Effects of nitric oxide synthase inhibition on cutaneous vasodilation in response to acupuncture stimulation in humans. Acupunct Med 2013;31:74–80.CrossRefPubMedGoogle Scholar
  40. 40.
    Sandberg M, Lundeberg T, Lindberg LG, Gerdle B. Effects of acupuncture on skin and muscle blood flow in healthy subjects. Eur J Appl Physiol 2003;90:114–119.CrossRefPubMedGoogle Scholar
  41. 41.
    Sandberg M, Lindberg LG, Gerdle B. Peripheral effects of needle stimulation (acupuncture) on skin and muscle blood flow in fibromyalgia. Eur J Pain 2004;8:163–171.CrossRefPubMedGoogle Scholar
  42. 42.
    Sandberg M, Larsson B, Lindberg LG, Gerdle B. Different patterns of blood flow response in the trapezius muscle following needle stimulation (acupuncture) between healthy subjects and patients with fibromyalgia and work-related trapezius myalgia. Eur J Pain 2005;9:497–510.CrossRefPubMedGoogle Scholar
  43. 43.
    Ma SX, Lee P, Anderson TL, Li XY, Jiang I. Response of local nitric oxide release to manual acupuncture and electrical heat in humans: Effects of reinforcement methods. Evid Based Complement Alternat Med 2017;2017:1–8.Google Scholar

Copyright information

© Chinese Association of the Integration of Traditional and Western Medicine and Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and Department of Obstetrics and Gynecology, David Geffen School of MedicineUniversity of California at Los Angeles and Harbor-UCLA Medical CenterTorranceUSA

Personalised recommendations