Electroacupuncture reduces chronic fibromyalgia pain through attenuation of transient receptor potential vanilloid 1 signaling pathway in mouse brains

Document Type: Original Article

Authors

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

2 Department of Anesthesiology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation

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

4 Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan

Abstract

Objective(s): Fibromyalgia pain is a mysterious clinical pain syndrome, characterized by inflammation in the brain, whose molecular mechanisms are still unknown. Females are more commonly affected by fibromyalgia, exhibiting symptoms such as widespread mechanical pain, immune dysfunction, sleep disturbances, and poor quality of life. Electroacupuncture (EA) has been used to relieve several types of pain, including fibromyalgia pain.
Materials and Methods: In the present study, we used dual injections of acidic saline into the gastrocnemius muscle to initiate a neural activation that resulted in fibromyalgia pain in mice. We used the Von Frey test to measure mechanical hyperalgesia and Western blot to measure protein levels.
Results: Results indicated that mechanical hyperalgesia can be induced in mice for 4 weeks, suggesting the induction of chronic fibromyalgia (CFM). Furthermore, continuous EA treatment reliably attenuated the mechanical hyperalgesia, but not in the sham control group. Results also suggested that the mechanical hyperalgesia can be prevented in mice with TRPV1 gene deletion. Mice with CFM showed increased expressions of TRPV1, Nav1.7, and Nav1.8 in the dorsal root ganglion (DRG) and the spinal cord (SC). The expression of TRPV1-associated molecules such as pPKA, pERK, and pCREB was also increased in the thalamus and somatosensory cortex (SSC) of the mice. All the aforementioned mechanisms were reversed by EA treatment and TRPV1 gene deletion.
Conclusion: Altogether, our results implied significant mechanisms of CFM and EA-analgesia that involve the regulation of the TRPV1 signaling pathway. These findings may be relevant to the evaluation and treatment of CFM.

Keywords


1. Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013; 369:448-457.
2. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009; 139:267-284.
3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288:1765-1769.
4. Apkarian AV, Baliki MN, Geha PY. Towards a theory of chronic pain. Prog Neurobiol 2009; 87:81-97.
5. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413:203-210.
6. English B. Neural and psychosocial mechanisms of pain sensitivity in fibromyalgia. Pain Manag Nurs 2014; 15:530-538.
7. Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014; 311:1547-1555.
8. Sluka KA, Kalra A, Moore SA. Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia. Muscle Nerve 2001; 24:37-46.
9. Yen LT, Hsieh CL, Hsu HC, Lin YW. Targeting ASIC3 for Relieving Mice Fibromyalgia Pain: Roles of Electroacupuncture, Opioid, and Adenosine. Sci Rep 2017; 7:46663-46677.
10. DeSantana JM, Sluka KA. Central mechanisms in the maintenance of chronic widespread noninflammatory muscle pain. Curr Pain Headache Rep 2008; 12:338-343.
11. Yang B, Yi G, Hong W, Bo C, Wang Z, Liu Y, et al. Efficacy of acupuncture on fibromyalgia syndrome: a meta-analysis. J Tradit Chin Med 2014; 34:381-391.
12. Stival RS, Cavalheiro PR, Stasiak CE, Galdino DT, Hoekstra BE, Schafranski MD. [Acupuncture in fibromyalgia: a randomized, controlled study addressing the immediate pain response]. Rev Bras Reumatol 2014; 54:431-436.
13. Moran MM. TRP Channels as Potential Drug Targets. Annu Rev Pharmacol Toxicol 2018; 58:309-330.
14. Moran MM, Szallasi A. Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. Br J Pharmacol 2018; 175:2185-2203.
15. Christoph T, Kogel B, Schiene K, Peters T, Schroder W. Investigation of TRPV1 loss-of-function phenotypes in TRPV1 Leu206Stop mice generated by N-ethyl-N-nitrosourea mutagenesis. Biochem Biophys Res Commun 2018; 500:456-461.
16. 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; 7:15679-15687.
17. Luo H, Xu IS, Chen Y, Yang F, Yu L, Li GX, et al. Behavioral and electrophysiological evidence for the differential functions of TRPV1 at early and late stages of chronic inflammatory nociception in rats. Neurochem Res 2008; 33:2151-2158.
18. Goldman N, Chen M, Fujita T, Xu Q, Peng W, Liu W, et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci 2010; 13:883-888.
19. Han JS. Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 2003; 26:17-22.
20. 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.
21. 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.
22. Lu KW, Yang J, Hsieh CL, Hsu YC, Lin YW. Electroacupuncture restores spatial learning and downregulates phosphorylated N-methyl-D-aspartate receptors in a mouse model of Parkinson’s disease. Acupunct Med 2017; 35:133-141.
23. Lin YW, Hsieh CL. Auricular electroacupuncture reduced inflammation-related epilepsy accompanied by altered TRPA1, pPKCalpha, pPKCepsilon, and pERk1/2 signaling pathways in kainic acid-treated rats. Mediators Inflamm 2014; 2014:493480.
24. 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; 6:22123-22133.
25. Littlejohn G, Guymer E. Neurogenic inflammation in fibromyalgia. Semin Immunopathol 2018; 40:291-300.
26. Rodriguez-Pinto I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia and cytokines. Immunol Lett 2014; 161:200-203.
27. Generaal E, Vogelzangs N, Macfarlane GJ, Geenen R, Smit JH, Dekker J, et al. Basal inflammation and innate immune response in chronic multisite musculoskeletal pain. Pain 2014; 155:1605-1612.
28. Uceyler N, Hauser W, Sommer C. Systematic review with meta-analysis: cytokines in fibromyalgia syndrome. BMC Musculoskelet Disord 2011; 12:245.
29. Rea K, Dinan TG, Cryan JF. The microbiome: A key regulator of stress and neuroinflammation. Neurobiol Stress 2016; 4:23-33.
30. Edwards JG. TRPV1 in the central nervous system: synaptic plasticity, function, and pharmacological implications. Prog Drug Res 2014; 68:77-104.
31. Marrone MC, Morabito A, Giustizieri M, Chiurchiu V, Leuti A, Mattioli M, et al. TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nat Commun 2017; 8:15292-15309.
32. Bair MJ, Wu J, Damush TM, Sutherland JM, Kroenke K. Association of depression and anxiety alone and in combination with chronic musculoskeletal pain in primary care patients. Psychosom Med 2008; 70:890-897.
33. Liedberg GM, Bjork M, Borsbo B. Self-reported nonrestorative sleep in fibromyalgia-relationship to impairments of body functions, personal function factors, and quality of life. J Pain Res 2015; 8:499-505.
34. Argoff CE. The coexistence of neuropathic pain, sleep, and psychiatric disorders: a novel treatment approach. Clin J Pain 2007; 23:15-22.
35. Sawaddiruk P, Paiboonworachat S, Chattipakorn N, Chattipakorn SC. Alterations of brain activity in fibromyalgia patients. J Clin Neurosci 2017; 38:13-22.
36. Yuksel E, Naziroglu M, Sahin M, Cig B. Involvement of TRPM2 and TRPV1 channels on hyperalgesia, apoptosis and oxidative stress in rat fibromyalgia model: Protective role of selenium. Sci Rep 2017; 7:17543-17554.
37. Maciel LY, da Cruz KM, de Araujo AM, Silva ZM, Badaue-Passos D Jr, Santana-Filho VJ, et al. Electroacupuncture reduces hyperalgesia after injections of acidic saline in rats. Evid Based Complement Alternat Med 2014; 2014:485043-485056.
38. Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain 2004; 108:237-247.
39. Strickland IT, Martindale JC, Woodhams PL, Reeve AJ, Chessell IP, McQueen DS. Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur J Pain 2008; 12:564-572.
40. Laird JM, Souslova V, Wood JN, Cervero F. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci 2002; 22:8352-8356.
41. Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci U S A 2007; 104:8520-8525.