Mediators, Receptors, and Signalling Pathways in the Anti-Inflammatory and Antihyperalgesic Effects of Acupuncture

John L McDonald, Allan W Cripps, Peter K Smith, John L McDonald, Allan W Cripps, Peter K Smith

Abstract

Acupuncture has been used for millennia to treat allergic diseases including both intermittent rhinitis and persistent rhinitis. Besides the research on the efficacy and safety of acupuncture treatment for allergic rhinitis, research has also investigated how acupuncture might modulate immune function to exert anti-inflammatory effects. A proposed model has previously hypothesized that acupuncture might downregulate proinflammatory neuropeptides, proinflammatory cytokines, and neurotrophins, modulating transient receptor potential vallinoid (TRPV1), a G-protein coupled receptor which plays a central role in allergic rhinitis. Recent research has been largely supportive of this model. New advances in research include the discovery of a novel cholinergic anti-inflammatory pathway activated by acupuncture. A chemokine-mediated proliferation of opioid-containing macrophages in inflamed tissues, in response to acupuncture, has also been demonstrated for the first time. Further research on the complex cross talk between receptors during inflammation is also helping to elucidate the mediators and signalling pathways activated by acupuncture.

Figures

Figure 1
Figure 1
Proposed model for the complex cross talk between various receptors and mediators in early phase response in allergic rhinitis. 1: nerve growth factor (NGF) activates tyrosine kinase A (TrkA) receptor which in turn increases production and release of substance P (SP). Activation of TrkA receptor also initiates signalling via the PI3K/PIP3 pathway to increase expression and sensitivity of transient receptor potential vallinoid (TRPV1) receptor. 2: chemokine receptors (CCR2, CCR3, and CXCR8) sensitize TRPV1 receptor via a PLCβ/PKC pathway. 3: TRPV1 receptor increases production and release of proinflammatory neuropeptides SP and CGRP which act synergistically to promote degranulation of primed mast cells. Histamine released by mast cells activates histamine 1 receptor (H1R) producing signalling via the phospholipase A2/lipoxygenase pathway to activate TRPV1, triggering early phase allergic inflammatory response. 4: chemokine receptors are heterologously desensitized by both adenosine (A2a) receptors and opioid receptors (MOR, DOR, and KOR). 5: Substance P is inhibited by met-enkephalin via Mu opioid receptors (MOR). A2a: adenosine 2a receptor, CCR2, CCR3: CC chemokine receptors 2 & 3, CXCR8: CXC chemokine receptor 8, PLCβ: phospholipase C β, PKC: protein kinase C, NGF: nerve growth factor, TRPV1: transient receptor potential vallinoid 1, TrkA: tyrosine kinase A receptor, H1R: histamine 1 receptor, SP: substance P, CGRP: calcitonin gene-related peptide, PI3K/PIP3: phosphatidylinositol 3 kinase/phosphatidylinositol phosphate 3 pathway, PLA2/LO: phospholipase A2/lipoxygenase pathway, MOR: Mu opioid receptor, DOR: delta opioid receptor, KOR: kappa opioid receptor, and MEK: met-enkephalin.
Figure 2
Figure 2
Receptor interactions potentially involved in the anti-inflammatory effects of acupuncture.

References

    1. McDonald J. L., Cripps A. W., Smith P. K., Smith C. A., Xue C. C., Golianu B. The anti-inflammatory effects of acupuncture and their relevance to allergic rhinitis: a narrative review and proposed model. Evidence-Based Complementary and Alternative Medicine. 2013;2013:12. doi: 10.1155/2013/591796.591796
    1. Li A., Lao L., Wang Y., et al. Electroacupuncture activates corticotrophin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation. BMC Complementary and Alternative Medicine. 2008;8, article 20 doi: 10.1186/1472-6882-8-20.
    1. Li A., Zhang R.-X., Wang Y., et al. Corticosterone mediates electroacupuncture-produced anti-edema in a rat model of inflammation. BMC Complementary and Alternative Medicine. 2007;7, article 27 doi: 10.1186/1472-6882-7-27.
    1. Du J.-Y., Fang J.-Q., Liang Y., Fang J.-F. Electroacupuncture attenuates mechanical allodynia by suppressing the spinal JNK1/2 pathway in a rat model of inflammatory pain. Brain Research Bulletin. 2014;108:27–36. doi: 10.1016/j.brainresbull.2014.06.004.
    1. Fang J.-Q., Du J.-Y., Liang Y., Fang J.-F. Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats. Molecular Pain. 2013;9(1, article 13) doi: 10.1186/1744-8069-9-13.
    1. Kim H.-W., Roh D.-H., Yoon S.-Y., et al. The anti-inflammatory effects of low- and high-frequency electroacupuncture are mediated by peripheral opioids in a mouse air pouch inflammation model. Journal of Alternative and Complementary Medicine. 2006;12(1):39–44. doi: 10.1089/acm.2006.12.39.
    1. Sekido R., Ishimaru K., Sakita M. Differences of electroacupuncture-induced analgesic effect in normal and inflammatory conditions in rats. American Journal of Chinese Medicine. 2003;31(6):955–965. doi: 10.1142/s0192415x03001491.
    1. Zhang S. P., Zhang J. S., Yung K. K. L., Zhang H. Q. Non-opioid-dependent anti-inflammatory effects of low frequency electroacupuncture. Brain Research Bulletin. 2004;62(4):327–334. doi: 10.1016/j.brainresbull.2003.10.002.
    1. Wang Y., Hackel D., Peng F., Rittner H. L. Long-term antinociception by electroacupuncture is mediated via peripheral opioid receptors in free-moving rats with inflammatory hyperalgesia. European Journal of Pain. 2013;17(10):1447–1457. doi: 10.1002/j.1532-2149.2013.00325.x.
    1. Huang C., Hu Z.-P., Long H., Shi Y.-S., Han J.-S., Wan Y. Attenuation of mechanical but not thermal hyperalgesia by electroacupuncture with the involvement of opioids in rat model of chronic inflammatory pain. Brain Research Bulletin. 2004;63(2):99–103. doi: 10.1016/j.brainresbull.2004.01.006.
    1. Huang C., Huang Z.-Q., Hu Z.-P., et al. Electroacupuncture effects in a rat model of complete Freund's adjuvant-induced inflammatory pain: antinociceptive effects enhanced and tolerance development accelerated. Neurochemical Research. 2008;33(10):2107–2111. doi: 10.1007/s11064-008-9721-x.
    1. Su T. F., Zhang L. H., Peng M., et al. Cannabinoid CB2 receptors contribute to upregulation of beta-endorphin in inflamed skin tissues by electroacupuncture. Molecular Pain. 2011;7, article 98 doi: 10.1186/1744-8069-7-98.
    1. Zhang X.-F., Zou Y., Zhao Y., Wang T.-H., Zhang W. Effects of eiectroacupuncture of ‘governor vessel’ acupoints on changes of BDNF in the cortical motor area of mice with spinal cord transection. Journal of Sichuan University. 2012;43(2):250–253.
    1. Shou Y., Yang Y., Xu M.-S., Zhao Y.-Q., Ge L.-B., Zhang B.-M. Electroacupuncture inhibition of hyperalgesia in rats with adjuvant arthritis: involvement of cannabinoid receptor 1 and dopamine receptor subtypes in striatum. Evidence-Based Complementary and Alternative Medicine. 2013;2013:10. doi: 10.1155/2013/393460.393460
    1. Fang J. Q., Fang J. F., Liang Y., Du J. Y. Electroacupuncture mediates extracellular signal-regulated kinase 1/2 pathways in the spinal cord of rats with inflammatory pain. BMC Complementary & Alternative Medicine. 2014;14(1, article 285) doi: 10.1186/1472-6882-14-285.
    1. Wang Y., Gehringer R., Mousa S. A., Hackel D., Brack A., Rittner H. L. CXCL10 controls inflammatory pain via opioid peptide-containing macrophages in electroacupuncture. PLoS ONE. 2014;9(4) doi: 10.1371/journal.pone.0094696.e94696
    1. Chen W.-H., Hsieh C.-L., Huang C.-P., et al. Acid-sensing ion channel 3 mediates peripheral anti-hyperalgesia effects of acupuncture in mice inflammatory pain. Journal of Biomedical Science. 2011;18(1, article 82) doi: 10.1186/1423-0127-18-82.
    1. Huang C.-P., Chen H.-N., Su H.-L., et al. Electroacupuncture reduces carrageenan- and CFA-induced inflammatory pain accompanied by changing the expression of Nav1.7 and Nav1.8, rather than Nav1.9, in mice dorsal root ganglia. Evidence-Based Complementary and Alternative Medicine. 2013;2013:8. doi: 10.1155/2013/312184.312184
    1. Kim H. N., Kim Y. R., Jang J. Y., Shin H. K., Choi B. T. Electroacupuncture inhibits phosphorylation of spinal phosphatidylinositol 3-kinase/Akt in a carrageenan-induced inflammatory rat model. Brain Research Bulletin. 2012;87(2-3):199–204. doi: 10.1016/j.brainresbull.2011.11.010.
    1. da Silva M. D., Bobinski F., Sato K. L., Kolker S. J., Sluka K. A., Santos A. R. IL-10 cytokine released from M2 macrophages is crucial for analgesic and anti-inflammatory effects of acupuncture in a model of inflammatory muscle pain. Molecular Neurobiology. 2015;51(1):19–31. doi: 10.1007/s12035-014-8790-x.
    1. Kim H. Y., Wang J., Lee I., Kim H. K., Chung K., Chung J. M. Electroacupuncture suppresses capsaicin-induced secondary hyperalgesia through an endogenous spinal opioid mechanism. Pain. 2009;145(3):332–340. doi: 10.1016/j.pain.2009.06.035.
    1. Hwang H. S., Yang E. J., Lee S. M., Lee S. C., Choi S. Antiallodynic effects of electroacupuncture combined with MK-801 treatment through the regulation of p35/p25 in experimental diabetic neuropathy. Experimental Neurobiology. 2011;20(3):144–152. doi: 10.5607/en.2011.20.3.144.
    1. Jiang Y.-L., Yin X.-H., Shen Y.-F., He X.-F., Fang J.-Q. Low frequency electroacupuncture alleviated spinal nerve ligation induced mechanical allodynia by inhibiting TRPV1 upregulation in ipsilateral undamaged dorsal root ganglia in rats. Evidence-Based Complementary and Alternative Medicine. 2013;2013:9. doi: 10.1155/2013/170910.170910
    1. Lee J. Y., Choi D. C., Oh T. H., Yune T. Y. Analgesic effect of acupuncture is mediated via inhibition of JNK activation in astrocytes after spinal cord injury. PLoS ONE. 2013;8(9) doi: 10.1371/journal.pone.0073948.e73948
    1. Yu J., Zhao C., Luo X. The effects of electroacupuncture on the extracellular signal-regulated kinase 1/2/P2X3 signal pathway in the spinal cord of rats with chronic constriction injury. Anesthesia & Analgesia. 2013;116(1):239–246. doi: 10.1213/ane.0b013e31826f0a4a.
    1. Hsu H.-C., Tang N.-Y., Lin Y.-W., Li T.-C., Liu H.-J., Hsieh C.-L. Effect of electroacupuncture on rats with chronic constriction injury-induced neuropathic pain. The Scientific World Journal. 2014;2014:9. doi: 10.1155/2014/129875.129875
    1. Wang H.-C., Zuo C.-T., Guan Y.-H. Research on receptors related to acupuncture analgesia and positron emission tomography radioligands: a review. Journal of Chinese Integrative Medicine. 2009;7(6):575–581. doi: 10.3736/jcim20090615.
    1. Park Y. C., Jo J. H., Hong K. E., Kang W. C., Choi S. M. Effect of acupuncture on nasal obstruction in patients with persistent allergic rhinitis: a randomized, controlled trial. The Journal of Korean Acupuncture & Moxibustion Society. 2005;22:229–239.
    1. Brinkhaus B., Ortiz M., Witt C. M., et al. Acupuncture in patients with seasonal allergic rhinitis: a randomized trial. Annals of Internal Medicine. 2013;158(4):225–234. doi: 10.7326/0003-4819-158-4-201302190-00002.
    1. Choi S. M., Park J. E., Li S.-S., et al. A multicenter, randomized, controlled trial testing the effects of acupuncture on allergic rhinitis. Allergy. 2013;68(3):365–374. doi: 10.1111/all.12053.
    1. Rao Y. Q., Han N. Y. Therapeutic effect of acupuncture on allergic rhinitis and its effects on immunologic function. Zhongguo Zhen Jiu. 2006;26:557–560.
    1. Xue C. C., An X., Cheung T. P., et al. Acupuncture for persistent allergic rhinitis: a randomised, sham-controlled trial. Medical Journal of Australia. 2007;187(6):337–341.
    1. Xue C. C., English R., Zhang J. J., da Costa C., Li C. G. Effect of acupuncture in the treatment of seasonal allergic rhinitis: a randomized controlled clinical trial. The American Journal of Chinese Medicine. 2002;30(1):1–11. doi: 10.1142/s0192415x0200020x.
    1. Sarin S., Undem B., Sanico A., Togias A. The role of the nervous system in rhinitis. The Journal of Allergy and Clinical Immunology. 2006;118(5):999–1014. doi: 10.1016/j.jaci.2006.09.013.
    1. Li Y.-M., Zhuang L.-X., Lai X.-S., Jiang G.-H. Effects of electroacupuncture on plasma vasoactive intestinal peptide and substance P in perennial allergic rhinitis patients. Zhen Ci Yan Jiu. 2007;32(2):136–138.
    1. Jung D., Lee S., Hong S. Effects of acupuncture and moxibustion in a mouse model of allergic rhinitis. Otolaryngology—Head and Neck Surgery. 2012;146(1):19–25. doi: 10.1177/0194599811421736.
    1. Hauswald B., Dill C., Boxberger J., Kuhlisch E., Zahnert T., Yarin Y. M. The effectiveness of acupuncture compared to loratadine in patients allergic to house dust mites. Journal of Allergy. 2014;2014:7. doi: 10.1155/2014/654632.654632
    1. Petti F. B., Liguori A., Ippoliti F. Study on cytokines IL-2, IL-6, IL-10 in patients of chronic allergic rhinitis treated with acupuncture. Journal of Traditional Chinese Medicine. 2002;22(2):104–111.
    1. Shiue H.-S., Lee Y.-S., Tsai C.-N., Hsueh Y.-M., Sheu J.-R., Chang H.-H. DNA microarray analysis of the effect on inflammation in patients treated with acupuncture for allergic rhinitis. Journal of Alternative and Complementary Medicine. 2008;14(6):689–698. doi: 10.1089/acm.2007.0669.
    1. Zheng M.-F., Lin C., Zheng L.-P., He F.-R. Effects of acupuncture-moxibustion on monocyte Th1/Th2 cytokine in peripheral blood of patients with perennial allergic rhinitis. Journal of Acupuncture and Tuina Science. 2010;8(2):85–88. doi: 10.1007/s11726-010-0085-9.
    1. Kim Y. R., Kim H. N., Ahn S. M., Choi Y. H., Shin H. K., Choi B. T. Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS ONE. 2014;9(2) doi: 10.1371/journal.pone.0090000.e90000
    1. Liang J., Lu J., Cui S. F., Wang J. R., Tu Y. Effect of acupuncture on expression of brain-derived neurotrophic factor gene and protein in frontal cortex and hippocampus of depression rats. Zhen Ci Yan Jiu. 2012;37(1):20–24.
    1. Lin D., Pena I. D. L., Lin L., Zhou S.-F., Borlongan C. V., Cao C. The neuroprotective role of acupuncture and activation of the BDNF signaling pathway. International Journal of Molecular Sciences. 2014;15(2):3234–3252. doi: 10.3390/ijms15023234.
    1. Sun H., Zhao H., Ma C., et al. Effects of electroacupuncture on depression and the production of glial cell line-derived neurotrophic factor compared with fluoxetine: a randomized controlled pilot study. Journal of Alternative and Complementary Medicine. 2013;19(9):733–739. doi: 10.1089/acm.2011.0637.
    1. Fang S. Y., Shen C. L. Neuropeptide innervation and neuroendocrine cells in allergic rhinitis and chronic hypertrophic rhinitis. Clinical and Experimental Allergy. 1998;28(2):228–232. doi: 10.1046/j.1365-2222.1998.00204.x.
    1. Figueroa J. M., Mansilla E., Suburo A. M. Innervation of nasal turbinate blood vessels in rhinitic and nonrhinitic children. American Journal of Respiratory and Critical Care Medicine. 1998;157(6):1959–1966. doi: 10.1164/ajrccm.157.6.9709019.
    1. Fischer A., Wussow A., Cryer A., et al. Neuronal plasticity in persistent perennial allergic rhinitis. Journal of Occupational and Environmental Medicine. 2005;47(1):20–25. doi: 10.1097/01.jom.0000150238.77663.49.
    1. Zhang N., Oppenheim J. J. Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems. Journal of Leukocyte Biology. 2005;78(6):1210–1214. doi: 10.1189/jlb.0405224.
    1. Gao W., Tang X., Chen Z., et al. Effects of acupuncture on CCL2 and CXCL8 expression and the subset of uNK cells in rats with embryo implantation failure. Evidence-Based Complementary and Alternative Medicine. 2013;2013:12. doi: 10.1155/2013/678390.678390
    1. Wei H., Yao X., Yang L., et al. Glycogen synthase kinase-3β is involved in electroacupuncture pretreatment via the cannabinoid CB1 receptor in ischemic stroke. Molecular Neurobiology. 2014;49(1):326–336. doi: 10.1007/s12035-013-8524-5.
    1. Zhou H., Zhang Z., Wei H., et al. Activation of STAT3 is involved in neuroprotection by electroacupuncture pretreatment via cannabinoid CB1 receptors in rats. Brain Research. 2013;1529:154–164. doi: 10.1016/j.brainres.2013.07.006.
    1. Rocha e Silva M. A brief survey of the history of inflammation. 1978. Agents and Actions. 1994;43(3-4):86–90.
    1. Dinh Q. T., Groneberg D. A., Peiser C., et al. Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung. Respiratory Physiology and Neurobiology. 2004;144(1):15–24. doi: 10.1016/j.resp.2004.08.001.
    1. Brokaw J. J., White G. W. Calcitonin gene-related peptide potentiates substance P-induced plasma extravasation in the rat trachea. Lung. 1992;170(2):85–93.
    1. Xin J.-J., Su Y.-S., Yang Z.-K., et al. Effects of electroacupuncture and regional thermal stimulation at ‘Zusanli’ (ST 36) on pain thresholds of TRPV 1 knock-out mice. Acupuncture Research. 2012;37(6):431–439.
    1. Shim W.-S., Tak M.-H., Lee M.-H., et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. The Journal of Neuroscience. 2007;27(9):2331–2337. doi: 10.1523/jneurosci.4643-06.2007.
    1. Zhang R.-X., Liu B., Qiao J.-T., et al. Electroacupuncture suppresses spinal expression of neurokinin-1 receptors induced by persistent inflammation in rats. Neuroscience Letters. 2005;384(3):339–343. doi: 10.1016/j.neulet.2005.05.001.
    1. Tracey K. J. Physiology and immunology of the cholinergic antiinflammatory pathway. The Journal of Clinical Investigation. 2007;117(2):289–296. doi: 10.1172/jci30555.
    1. Torres-Rosas R., Yehia G., Peña G., et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nature Medicine. 2014;20(3):291–295. doi: 10.1038/nm.3479.
    1. Goldman N., Chen M., Fujita T., et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nature Neuroscience. 2010;13(7):883–888. doi: 10.1038/nn.2562.
    1. Takano T., Chen X., Luo F., et al. Traditional acupuncture triggers a local increase in adenosine in human subjects. Journal of Pain. 2012;13(12):1215–1223. doi: 10.1016/j.jpain.2012.09.012.
    1. Tominaga M., Tominaga T. Structure and function of TRPV1. Pflugers Archiv. 2005;451(1):143–150. doi: 10.1007/s00424-005-1457-8.
    1. Little J. W., Ford A., Symons-Liguori A. M., et al. Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states. Brain. 2015;138(1):28–35. doi: 10.1093/brain/awu330.
    1. Ai M. K., Guan X. M., Zhu C. G., Vacca L. L. The influence of electroacupuncture and morphine on Substance P (SP) Enkephalin (ENK) and Acetylcholine Esterase (AChE) in the spinal cord of rats. Zhen Ci Yan Jiu. 1986;11:96–105.
    1. Kondo I., Marvizon J. C. G., Song B. B., et al. Inhibition by spinal μ- and δ-opioid agonists of afferent-evoked substance P release. The Journal of Neuroscience. 2005;25(14):3651–3660. doi: 10.1523/jneurosci.0252-05.2005.
    1. Keeble J., Russell F., Curtis B., Starr A., Pinter E., Brain S. D. Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis & Rheumatism. 2005;52(10):3248–3256. doi: 10.1002/art.21297.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren