Acupuncture has been clinically recommended as a method of pain relief by the World Health Organization and is widely used by medical doctors. Fibromyalgia (FM) pain has a complex physiological and psychological origin and can be pharmacologically treated with duloxetine, milnacipran and pregabalin. However, these drugs produce undesirable side effects, such as headaches, nausea and diarrhoea. Acupuncture may serve as an effective alternative treatment for pain relief with few side effects.
Aims:
We hypothesised that acupuncture would reduce FM pain by influencing transient receptor potential cation channel subfamily V member 1 (TRPV1) and the downstream phosphorylated extracellular signal-regulated kinases (pERK), which are located in the central thalamus, amygdala and cortex.
Methods:
A FM mouse model was established by injecting two doses of acid saline into 32 female C57/B6 mice. The mice were then assigned to different subgroups (n=8 each) and treated with electroacupuncture (EA) or EA sham control. TRPV1 and pERK expression levels were measured using Western blotting and immunohistochemistry.
Results:
Our results demonstrated that the expression of TRPV1 and pERK in the thalamus, amygdala and somatosensory cortex was normal in the control mice, but significantly increased in FM mice; these FM-induced changes in expression were attenuated by EA.
Conclusion:
Our data suggest that EA can reverse the central sensitisation of the TRPV1-ERK signalling pathway in the mouse brain. Thus, our findings provide mechanistic evidence supporting the potential therapeutic efficacy of EA for treating FM pain.
WolfeFClauwDJFitzcharlesMA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res2010; 62: 600–610.
2.
YangBYiGHongW, et al. Efficacy of acupuncture on fibromyalgia syndrome: a meta-analysis. J Tradit Chin Med2014; 34: 381–391.
3.
VasJSantos-ReyKNavarro-PabloR, et al. Acupuncture for fibromyalgia in primary care: a randomised controlled trial. Acupunct Med2016; 34: 257–266.
4.
DeSantanaJMda CruzKMSlukaKA. Animal models of fibromyalgia. Arthritis Res Ther2013; 15: 222.
5.
CaterinaMJLefflerAMalmbergAB, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science2000; 288: 306–313.
MezeyETóthZECortrightDN, et al. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci U S A2000; 97: 3655–3660.
8.
ChristophTBahrenbergGDe VryJ, et al. Investigation of TRPV1 loss-of-function phenotypes in transgenic shRNA expressing and knockout mice. Mol Cell Neurosci2008; 37: 579–589.
9.
DavisJBGrayJGunthorpeMJ, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature2000; 405:183–187.
10.
LuoHChengJHanJS, et al. Change of vanilloid receptor 1 expression in dorsal root ganglion and spinal dorsal horn during inflammatory nociception induced by complete Freund’s adjuvant in rats. Neuroreport2004; 15: 655–658.
11.
JiRRWoolfCJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis2001; 8: 1–10.
12.
JiRRSamadTAJinSX, et al. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron2002; 36: 57–68.
LinJGHsiehCLLinYW. Analgesic effect of electroacupuncture in a mouse fibromyalgia model: roles of TRPV1, TRPV4, and pERK. PLoS One2015; 10(6):e0128037.
15.
AdwanikarHKarimFGereauRW. Inflammation persistently enhances nocifensive behaviors mediated by spinal group I mGluRs through sustained ERK activation. Pain2004; 111: 125–135.
16.
KawasakiYKohnoTZhuangZY, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci2004; 24: 8310–8321.
17.
MaWQuirionR. The ERK/MAPK pathway, as a target for the treatment of neuropathic pain. Expert Opin Ther Targets2005; 9: 699–713.
18.
LiaoYLiXLiN, et al. Electroacupuncture protects against articular cartilage erosion by inhibiting mitogen-activated protein kinases in a rat model of osteoarthritis. Acupunct Med2016; 34: 290–295.
19.
WuCLiCZhouG, et al. Effects of electroacupuncture on the cortical extracellular signal regulated kinase pathway in rats with cerebral ischaemia/reperfusion. Acupunct Med2017; 35.
20.
KimSYLeeHLeeH, et al. An observational study on the costs and consequences of acupuncture for the management of chronic low back pain in Korean patients. Acupunct Med2015; 33: 148–153.
21.
Kurath-KollerSBauchingerSSperlD, et al. Use of NADA ear acupuncture in an adolescent patient with phantom limb pain after surgery for osteosarcoma. Acupunct Med2015; 33: 82–84.
22.
CayirYOzdemirGCelikM, et al. Acupuncture decreases matrix metalloproteinase-2 activity in patients with migraine. Acupunct Med2014; 32: 376–380.
23.
ChoowanthanapakornMLuKWYangJ, et al. Targeting TRPV1 for body weight control using TRPV1(-/-) mice and electroacupuncture. Sci Rep2015; 5: 17366.
24.
KuoCTLinYWTangNY, et al. Electric stimulation of the ears ameliorated learning and memory impairment in rats with cerebral ischemia-reperfusion injury. Sci Rep2016; 6: 20381.
25.
HanJS. Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci2003; 26: 17–22.
26.
HsiehYLHongCZLiuSY, et al. Acupuncture at distant myofascial trigger spots enhances endogenous opioids in rabbits: a possible mechanism for managing myofascial pain. Acupunct Med2016; 34: 302–309.
27.
JiangQYWangMYLiL, et al. Electroacupuncture relieves labour pain and influences the spinal dynorphin/κ-opioid receptor system in rats. Acupunct Med2016; 34: 223–228.
28.
GoldmanNChenMFujitaT, et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci2010; 13: 883–888.
29.
ShinbaraHNagaokaSIzutaniY, et al. Contribution of adenosine to the increase in skeletal muscle blood flow caused by manual acupuncture in rats. Acupunct Med2017; 35: 284–288.
30.
LuKWHsuCKHsiehCL, et al. Probing the effects and mechanisms of electroacupuncture at ipsilateral or contralateral ST36-ST37 acupoints on CFA-induced inflammatory pain. Sci Rep2016; 6: 22123.
31.
LuKWHsiehCLYangJ, et al. Effects of electroacupuncture in a mouse model of fibromyalgia: role of N-methyl-D-aspartate receptors and related mechanisms. Acupunct Med2017; 35: 59–68.
32.
WuSYChenWHHsiehCL, et al. Abundant expression and functional participation of TRPV1 at Zusanli acupoint (ST36) in mice: mechanosensitive TRPV1 as an “acupuncture-responding channel”. BMC Complement Altern Med2014; 14: 96.
33.
LuKWYangJHsiehCL, et al. Electroacupuncture restores spatial learning and downregulates phosphorylated N-methyl-D-aspartate receptors in a mouse model of Parkinson’s disease. Acupunct Med2017; 35: 133–141.
34.
ChengSJChenCCYangHW, et al. Role of extracellular signal-regulated kinase in synaptic transmission and plasticity of a nociceptive input on capsular central amygdaloid neurons in normal and acid-induced muscle pain mice. J Neurosci2011; 31: 2258–2270.
35.
ChenWKLiuIYChangYT, et al. Ca(v)3.2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain. J Neurosci2010; 30: 10360–10368.
36.
BreeseNMGeorgeACPauersLE, et al. Peripheral inflammation selectively increases TRPV1 function in IB4-positive sensory neurons from adult mouse. Pain2005; 115: 37–49.
37.
KasamaSKawakuboMSuzukiT, et al. RNA interference-mediated knock-down of transient receptor potential vanilloid 1 prevents forepaw inflammatory hyperalgesia in rat. Eur J Neurosci2007; 25: 2956–2963.
38.
JiRRBabaHBrennerGJ, et al. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci1999; 2: 1114–1119.
39.
AleyKOMartinAMcMahonT, et al. Nociceptor sensitization by extracellular signal-regulated kinases. J Neurosci2001; 21: 6933–6939.
LiuYLiuYJinH, et al. Cold stress-induced brain injury regulates TRPV1 channels and the PI3K/AKT signaling pathway. Brain Res2017; 1670: 201–207.
42.
ZhangRLaoLRenK, et al. Mechanisms of acupuncture-electroacupuncture on persistent pain. Anesthesiology2014; 120: 482–503.
43.
MarroneMCMorabitoAGiustizieriM, et al. TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nat Commun2017; 8: 15292.
44.
PremkumarLSAhernGP. Induction of vanilloid receptor channel activity by protein kinase C. Nature2000; 408: 985–990.
45.
AmadesiSCottrellGSDivinoL, et al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. J Physiol2006; 575: 555–571.
46.
YamamotoHKawadaTKamiyaA, et al. Involvement of the mechanoreceptors in the sensory mechanisms of manual and electrical acupuncture. Auton Neurosci2011; 160: 27–31.
