Electroacupuncture attenuates chronic fibromyalgia pain through the phosphorylated phosphoinositide 3-kinase signaling pathway in the mouse brain

Document Type: Original Article

Authors

1 Center for General Education, Chung Yuan Christian University, Taoyuan 32023, Taiwan

2 College of Chinese Medicine, School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan

3 College of Chinese Medicine, Graduate Institute of Acupuncture Science, China Medical University, Taichung 40402, Taiwan

Abstract

Objective(s): Fibromyalgia (FM) is a central nervous system disorder characterized by widespread mechanical hyperalgesia due to unknown mechanisms. Several inflammatory mediators, such as interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor, are increased in the serum of FM patients. Although medications including pregabalin, duloxetine, and milnacipran are used to treat FM, the results are unsatisfying. In the present study we assessed whether electroacupuncture (EA) can reduce chronic FM pain and then proposed an underlying mechanism for this effect.
Materials and Methods: Chronic FM pain was induced in mice by dual acid saline injection lasting up to 4 weeks.
Results: Chronic FM pain was treated by EA manipulation, but not in the sham operated group. Phosphorylated phosphatidylinositol 3-kinase (pPI3K), protein kinase B, mechanistic target of rapamycin, and nuclear factor kappa-light-chain-enhancer of activated B cells were unaltered in the mouse dorsal root ganglion (DRG) and spinal cord (SC) after inducing FM and administering EA treatment. The pPI3K-associated nociceptive signaling pathway was increased in the thalamus of FM mice, but reversed by EA. Similar results were observed in the mouse somatosensory cortex.
Conclusion: These data suggest that EA has a significant effect on a signaling pathway in brain areas of FM mice. These findings suggest the value of EA for clinical practice.

Keywords

Main Subjects


1. English B. Neural and psychosocial mechanisms of pain sensitivity in fibromyalgia. Pain Manag Nurs 2014; 15:530-538.
2. Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014; 311:1547-1555.
3. Dadabhoy D, Crofford LJ, Spaeth M, Russell IJ, Clauw DJ. Biology and therapy of fibromyalgia. Evidence-based biomarkers for fibromyalgia syndrome. Arthritis Res Ther 2008; 10:211.
4. Panerai AE, Vecchiet J, Panzeri P, Meroni P, Scarone S, Pizzigallo E, et al. Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report. Clin J Pain 2002; 18:270-273.
5. Gomez Del Pulgar T, De Ceballos ML, Guzman M, Velasco G. Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 2002; 277:36527-36533.
6. Deladeriere A, Gambardella L, Pan D, Anderson KE, Hawkins PT, Stephens LR. The regulatory subunits of PI3Kgamma control distinct neutrophil responses. Sci Signal 2015; 8:ra8.
7. Rubashkin MG, Cassereau L, Bainer R, DuFort CC, Yui Y, Ou G, et al. Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate. Cancer Res 2014; 74:4597-4611.
8. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307:1098-1101.
9. Ouyang ZH, Wang WJ, Yan YG, Wang B, Lv GH. The PI3K/Akt pathway: a critical player in intervertebral disc degeneration. Oncotarget 2017; 8:57870-57881.
10. Liao HY, Ho WC, Chen CC, Lin JG, Chang CC, Chen LY, et al. Clinical evaluation of acupuncture as treatment for complications of cerebrovascular accidents: a randomized, sham-controlled, subject- and assessor-blind trial. Evid Based Complement Alternat Med 2017; 2017:7498763.
11. Lin YW, Hsieh CL. Electroacupuncture at Baihui acupoint (GV20) reverses behavior deficit and long-term potentiation through N-methyl-d-aspartate and transient receptor potential vanilloid subtype 1 receptors in middle cerebral artery occlusion rats. J Integr Neurosci 2010; 9:269-282.
12. Liao HY, Hsieh CL, Huang CP, Lin YW. Electroacupuncture attenuates CFA-induced inflammatory pain by suppressing Nav1.8 through S100B, TRPV1, opioid, and adenosine pathways in mice. Sci Rep 2017; 7:42531.
13. Yen LT, Hsieh CL, Hsu HC, Lin YW. Targeting ASIC3 for relieving mice fibromyalgia pain: roles of electroacupuncture, opioid, and adenosine. Sci Rep 2017; 7:46663.
14. Lu KW, Hsu CK, Hsieh CL, Yang J, Lin YW. Probing the effects and mechanisms of electroacupuncture at ipsilateral or contralateral ST36-ST37 acupoints on CFA-induced inflammatory pain. Sci Rep 2016; 6:22123.
15. Liao HY, Hsieh CL, Huang CP, Lin YW. Electroacupuncture attenuates induction of inflammatory pain by regulating opioid and adenosine pathways in mice. Sci Rep 2017; 7:15679.
16. Andersson SA, Ericson T, Holmgren E, Lindqvist G. Electro-acupuncture and pain threshold. Lancet 1973; 2:564.
17. Han JS. Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 2003; 26:17-22.
18. Chang FC, Tsai HY, Yu MC, Yi PL, Lin JG. The central serotonergic system mediates the analgesic effect of electroacupuncture on ZUSANLI (ST36) acupoints. J Biomed Sci 2004; 11:179-185.
19. Kiser RS, Khatami MJ, Gatchel RJ, Huang XY, Bhatia K, Altshuler KZ. Acupuncture relief of chronic pain syndrome correlates with increased plasma met-enkephalin concentrations. Lancet 1983; 2:1394-1396.
20. Clement-Jones V, McLoughlin L, Tomlin S, Besser GM, Rees LH, Wen HL. Increased beta-endorphin but not met-enkephalin levels in human cerebrospinal fluid after acupuncture for recurrent pain. Lancet 1980; 2:946-949.
21. Mendieta D, De la Cruz-Aguilera DL, Barrera-Villalpando MI, Becerril-Villanueva E, Arreola R, Hernandez-Ferreira E, et al. IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients. J Neuroimmunol 2016; 290:22-25.
22. Tsilioni I, Russell IJ, Stewart JM, Gleason RM, Theoharides TC. Neuropeptides CRH, SP, HK-1, and inflammatory cytokines IL-6 and TNF are increased in serum of patients with fibromyalgia syndrome, implicating mast cells. J Pharmacol Exp Ther 2016; 356:664-672.
23. Ohgidani M, Kato TA, Hosoi M, Tsuda M, Hayakawa K, Hayaki C, et al. Fibromyalgia and microglial TNF-alpha: Translational research using human blood induced microglia-like cells. Sci Rep 2017; 7:11882.
24. Jiang SP, Zhang ZD, Kang LM, Wang QH, Zhang L, Chen HP. Celecoxib reverts oxaliplatin-induced neuropathic pain through inhibiting PI3K/Akt2 pathway in the mouse dorsal root ganglion. Exp Neurol 2016; 275 Pt 1:11-16.
25. Wigerblad G, Huie JR, Yin HZ, Leinders M, Pritchard RA, Koehrn FJ, et al. Inflammation-induced GluA1 trafficking and membrane insertion of Ca(2+) permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A. Exp Neurol 2017; 293:144-158.
26. Liu A, Wang X, Wang H, Lv G, Li Y, Li H. Delta-opioid receptor inhibition prevents remifentanil-induced post-operative hyperalgesia via regulating GluR1 trafficking and AMPA receptor function. Exp Ther Med 2018; 15:2140-2147.
27. Guo JR, Wang H, Jin XJ, Jia DL, Zhou X, Tao Q. Effect and mechanism of inhibition of PI3K/Akt/mTOR signal pathway on chronic neuropathic pain and spinal microglia in a rat model of chronic constriction injury. Oncotarget 2017; 8:52923-52934.
28. Pritchard RA, Falk L, Larsson M, Leinders M, Sorkin LS. Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation. Pain 2016; 157:137-146.
29. Xie X, Ma L, Xi K, Zhang W, Fan D. MicroRNA-183 suppresses neuropathic pain and expression of AMPA receptors by targeting mTOR/VEGF signaling pathway. Cell Physiol Biochem 2017; 41:181-192.
30. Kwon M, Han J, Kim UJ, Cha M, Um SW, Bai SJ, et al. Inhibition of mammalian target of rapamycin (mTOR) signaling in the insular cortex alleviates neuropathic pain after peripheral nerve injury. Front Mol Neurosci 2017; 10:79.
31. Chen Q, Mo R, Wu N, Zou X, Shi C, Gong J, et al. Berberine ameliorates diabetes-associated cognitive decline through modulation of aberrant inflammation response and insulin signaling pathway in DM rats. Front Pharmacol 2017; 8:334.