Acupuncture and electroacupuncture (EA) are widely applied as non-invasive treatment for acute and chronic pain. In the last decade, mechanisms of EA analgesia in inflammatory pain have been extensively studied (1-4).
A recent study by Liao et al. (5) investigated mechanisms of EA in a rodent model of inflammatory pain. The authors showed that intraperitoneal injection of the opioid-specific agonist endomorphin reduced mechanical and thermal hyperalgesia in inflammatory pain. Meanwhile, intraperitoneal injection of naloxone into the acupoint ST36 blocked the analgesic effects of EA. It is known that in inflamed tissues, EA activates immune cells such as lymphocytes, monocytes/macrophages and granulocyte (6,7). Furthermore, EA promotes the release of different endogenous opiates in a frequency-dependent manner (8). In rats, low-frequency (2 Hz) EA at ST36 stimulated the release of β-endorphin, enkephalin and endomorphin, whereas high-frequency (100 Hz) EA stimulated dynorphin to inhibit nociception (9,10). These findings have also been verified in humans (11). In addition, pulse width of EA influences its analgesic effect as well (12). Consistent with these findings, low- and high-frequency EA are mediated by µ-/δ-receptors and k-receptors, respectively under physiological conditions (10,13). However, in pathological conditions such as CFA/carrageenan-induced inflammatory pain rats, µ- and δ-receptors but not κ-receptors seem to be involved in EA analgesia (14,15). Further studies showed that lesions of the arcuate nuclei abolished low-frequency EA induced analgesia but not high-frequency EA, whereas lesions of the parabrachial nuclei attenuated high-frequency EA induced analgesia but not low-frequency EA (16,17). It appears that low- and high-frequency EA-induced analgesia may be mediated by different brain areas expressing opioid receptors.
Besides opioid peptides, various other signal molecules are implicated in acupuncture analgesia, including cholecystokinin octapeptide, 5-hydroxytryptamine, noradrenalin, glutamate etc. (18). Recently, increasing evidence revealed that adenosine A1 receptors participate in anti-nociception in peripheral, spinal and supraspinal levels (19,20). In 2010, Goldman et al. (21) first demonstrated that adenosine acting on A1 receptors in sensory afferents of ascending nerves mediated the anti-nociceptive actions of acupuncture. In the study by Liao et al. (5), researchers showed that administration of adenosine A1 receptor agonist at ST36 attenuated inflammatory pain behaviors, while an intramuscular injection of rolofylline, an adenosine A1 receptor antagonist, blocked the analgesic effects of EA. The authors further revealed that expression of the astrocyte marker GFAP, the microglia marker Iba-1, and associated proteins S100B and RAGE dramatically increased in the dorsal root ganglion and spinal dorsal horn of CFA-treated mice, which were reversed by EA.
Spinal astrocytes and microglia are involved in the induction and development of inflammatory pain (22-24). Combinative application of minocycline, a microglial inhibitor, enhanced EA’s analgesia effects in CFA-induced monoarthritic rat (25,26). EA stimulation at GB30 and GB34 markedly inhibited CFA-induced behavioral hypersensitivity, attenuated astrocyte and microglia activation, and upregulated TNF-α, IL-1β and IL-6 mRNA levels in the spinal cord (27,28). These findings suggest that analgesic effects of EA at least partially result from inhibiting spinal glial activities and proinflammatory cytokine production.
In conclusion, the study by Liao et al. (5) reveals the roles of glia/neuropeptide/adenosine in the analgesic effects of EA, and provides insight on mechanisms underlying EA’s therapeutic effects against inflammatory pain. Further investigation is required for elucidating detailed interactions between these molecular changes and EA stimulation.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Mayer DJ, Price DD, Raffi A. Antagonism of acupuncture analgesia in man by narcotic antagonist naloxone. Brain Res 1977;121:368-72. [Crossref] [PubMed]
- Basbaum AI, Jessell TM. The perception of pain. In: Kandel ER, Schwartz JH, Jessell TM, editors. Principles of Neural Science. McGraw-Hall. 2001.
- Fields HL, Basbaum AI, Heinricher MM. Central nervous system mechanisms of pain modulation. In: Wall & Melzack's Textbook of Pain. Fifth ed. Elsevier. 2005.
- Sekido R, Ishimaru K, Sakita M. Differences of electroacupuncture-induced analgesic effect in normal and inflammatory conditions in rats. Am J Chin Med 2003;31:955-65. [Crossref] [PubMed]
- Liao HY, Hsieh CL, Huang CP, et al. Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice. Sci Rep 2017;7:42531. [Crossref] [PubMed]
- Cabot PJ, Carter L, Gaiddon C, et al. Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats. J Clin Invest 1997;100:142-8. [Crossref] [PubMed]
- Rittner HL, Brack A, Machelska H, et al. Opioid peptide-expressing leukocytes:Identification, recruitment, and simultaneously increasing inhibition of inflammatory pain. Anesthesiology 2001;95:500-8. [Crossref] [PubMed]
- Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med 1995;332:1685-90. [Crossref] [PubMed]
- Fei H, Xie GX, Han JS. Low and high frequency electroacupuncture stimulation release [Met5] enkephalin and dynorphin A in rat spinal cord. Sci Bull China 1987;32:1496-501.
- Han JS. Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 2003;26:17-22. [Crossref] [PubMed]
- Han JS, Chen XH, Sun SL, et al. Effect of low- and high-frequency TENS on Met-enkephalin-Arg-Phe and dynorphin A immunoreactivity in human lumbar CSF. Pain 1991;47:295-8. [Crossref] [PubMed]
- Lao L, Zhang RX, Zhang G, et al. A parametric study of electroacupuncture on persistent hyperalgesia and Fos protein expression in rats. Brain Res 2004;1020:18-29. [Crossref] [PubMed]
- Wang Y, Zhang Y, Wang W, et al. Effects of synchronous or asynchronous electroacupuncture stimulation with low versus high frequency on spinal opioid release and tail flick nociception. Exp Neurol 2005;192:156-62. [Crossref] [PubMed]
- Zhang RX, Lao L, Wang L, et al. Involvement of opioid receptors in electroacupuncture produced anti-hyperalgesia in rats with peripheral inflammation. Brain Res 2004;1020:12-7. [Crossref] [PubMed]
- Yang EJ, Koo ST, Kim YS, et al. Contralateral electroacupuncture pretreatment suppresses carrageenan-induced inflammatory pain via the opioid-mu receptor. Rheumatol Int 2011;31:725-30. [Crossref] [PubMed]
- Wang Q, Mao L, Han J. The arcuate nucleus of hypothalamus mediates low but not high frequency electroacupuncture analgesia in rats. Brain Res 1990;513:60-6. [Crossref] [PubMed]
- Wang Q, Mao L, Han J. The role parabrachial nucleus in high frequency electroacupuncture analgesia in rats. Chin J Physiol Sci. 1991;7:363-371.
- Zhao ZQ. Neural mechanism underlying acupuncture analgesia. Prog Neurobiol 2008;85:355-75. [Crossref] [PubMed]
- Sawynok J. Adenosine receptor activation and nociception. Eur J Pharmacol 1998;347:1-11. [Crossref] [PubMed]
- Eisenach JC, Hood DD, Curry R, et al. Intrathecal but not intravenous opioids release adenosine from the spinal cord. J Pain 2004;5:64-8. [Crossref] [PubMed]
- Goldman N, Chen M, Fujita T, et al. Adenosine a1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci 2010;13:883-8. [Crossref] [PubMed]
- Li YY, Wei XH, Lu ZH, et al. Src/p38 MAPK pathway in spinal microglia is involved in mechanical allodynia induced by peri-sciatic administration of recombinant rat TNF-α. Brain Res Bull 2013;96:54-61. [Crossref] [PubMed]
- Ma JY, Zhao ZQ. The involvement of glia in the long-term plasticity of spinal dorsal horn of rat. Neuroreport 2002;13:1781-4. [Crossref] [PubMed]
- Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115:71-83. [Crossref] [PubMed]
- Watkins LR, Hutchinson MR, Ledeboer A, et al. Norman Cousins Lecture. Glia as the "bad guys": implications for improving clinical pain control and the clinical utility of opioids. Brain Behav Immun 2007;21:131-46. [Crossref] [PubMed]
- Sun S, Cao H, Han M, et al. Evidence for suppression of electroacupuncture on spinal glial activation and behavioral hypersensitivity in a rat model of monoarthritis. Brain Res Bull 2008;75:83-93. [Crossref] [PubMed]
- Shan S, Qi-Liang MY, Hong C, et al. Is functional state of spinal microglia involved in the anti-allodynic and anti-hyperalgesic effects of electroacupuncture in rat model of monoarthritis? Neurobiol Dis 2007;26:558-68. [Crossref] [PubMed]
- Mi WL, Mao-Ying QL, Wang XW, et al. Involvement of spinal neurotrophin-3 in electroacupuncture analgesia and inhibition of spinal glial activation in rat model of monoarthritis. J Pain 2011;12:974-84. [Crossref] [PubMed]
Cite this article as: Liu QY, Xu LC, Yi M. Anti-nociceptive mechanisms of electroacupuncture in inflammatory pain. AME Med J 2017;2:82.