本研究在carrageenan 所誘發的發炎疼痛模型下，探討以電針足三
里減輕小鼠發炎性疼痛與鈉離子通道之間的相關機轉。在電針足三里 後，藉由觀察小鼠的疼痛行為，可見機械性及溫度性痛覺敏感程度明顯 減少；在免疫螢光染色法及西方墨點分析法的研究結果顯示，電針可明 顯調降Nav1.7 及 Nav1.8 在發炎模式中的過度表現，但 Nav1.9 則無顯著 性差異。因此我們根據研究結果推論電針足三里減輕發炎疼痛的療效機 轉，和調控鈉離子通道中Nav 1.7 與 Nav 1.8 的表現相關，但與 Nav 1.9 則較無相關性。
第七章 參考文獻
1. Foulkes T, Wood JN. Pain genes. PLoS genetics. 2008;4(7):e1000086.
2. Sharif-Naeini R, Basbaum AI. Targeting pain where it resides ... In the brain. Sci Transl Med. 2011 12;3(65):65.
3. Mogil JS. Animal models of pain: progress and challenges. Nature reviews Neuroscience. 2009;10(4):283-294.
4. Lakhmir S Chawla, Amirali Nader, Todd Nelson, Trusha Govindji, Ryan Wilson, Sonia Szlyk, Aline Nguyen,Christopher Junker, Michael G
Seneff. Utilization of base deficit and reliability of base deficit as a surrogate for serum lactate in the peri-operative setting. BCM Anesthesiol. 2010 Sep 9;10(1):16
5. Walder RY, Gautam M, Wilson SP, Benson CJ, Sluka KA. Selective targeting of ASIC3 using artificial miRNAs inhibits primary and
secondary hyperalgesia after muscle inflammation. Pain. 2011;152(10):
2348-2356.
6. Dubner KRaR. Inflammatory Models of Pain and Hyperalgesia. Animal Models of Pain. 1999;40(3):111-118.
7. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267-284.
8. Wang W, Gu J, Li YQ, Tao YX. Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain?
Molecular pain. 2011;7:16.
9. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and Molecular Mechanisms of Pain. 2009;139(2):267-284.
10. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature.
2001 Sep 13;413(6852):203-210.
11. 林佑穗、袁宗凡編譯：Guyton & Hall 新編醫用生理學. 2005:609-612.
12. KA M. Assessingmechanicalallodynia in the ratpaw with
anewelectronicalgometer. Journal of Neuroscience Methods. 1896;84 (1-2):41-47.
13. K. Hargreaves RD, F. Brown, C. Flores, J. Joris. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.
Pain. 1988;32(1):77-88.
14. Eddt NB, Touchberry CF,Lieberman JE. Synthetic analgesics;
methadone isomers and derivatives J Pharmacol Exp Ther.
1950 Feb;98(2):121-137.
15. Gary J, Bennett Y-KX. Aperipheral mononeuropathy in rat that
produces disorders of pain sensation like those seen in man. Pain. 1988;
33( 1):87-107.
16. Mogil JS. Animal models of pain：progress and challenges. Nat Rev Neurosci. 2009 Apr;10(4):283-294.
17. Zhao ZQ. Neural mechanism underlying acupuncture analgesia. Progress in neurobiology. 2008;85(4):355-375.
18. 黃維三：針灸科學，2000:265-275.
19. 林昭庚：新編採圖針灸學，1999:739-754.
20. Chen J-GLW. acupuncture analgesia in clinical trials. American journal of chinese medicine. 2009;37(1):1-18.
21. Mark D, Baker and John N,Wood. Involvement of Na+ channels in pain pathway. TRENDS in Pharmacological Sciences. 2001;22(1) :27-31.
22. Momin A, Wood JN. Sensory neuron voltage-gated sodium channels as analgesic drug targets. Current opinion in neurobiology.2008;18(4):
383-388.
23. Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception: Implications for mechanisms of pain. Pain. 2007;131(3):
243-257.
24. Rush AM, Cummins TR, Waxman SG. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. The Journal of physiology. 2007;579(Pt 1):1-14.
25. Gold MS, Reichling DB, Shuster MJ,Levine JD. Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptor. Proc Natl Acad Sci USA. 1996 Feb 6;93(3):1108-12.
26. Zhang YH, Vasko MR, Nicol GD. Ceramide, a putative second
messenger for nerve growth factor, modulates the TTX-resistant Na+
current and delayed rectifier K+ current in rat sensory neurons. The Journal of physiology. 2002;544(2):385-402.
27. 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(3):237-247.
28. 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(5):564-572.
29. Leffler A HR, Dib-Hajj SD, Waxman SG, Cummins TR.
Pharmacological properties of neuronal TTX-resistant sodium channels and the role of a critical serine pore residue. Pflugers Arch. 2005;451(3):
454-463.
30. Tate S BS, Hick C, Trezise D, John V, Mannion RJ, et al. . Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons. Nat Neurosci. 1998;1:653-655.
31. Amaya F, Wang H, Costigan M, Allchorne AJ, Hatcher JP, Egerton J, Stean T, Morisset V, Grose D, Gunthorpe MJ, Chessell IP, Tate S, Green PJ, Woolf CJ. The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity. The Journal of
neuroscience : the official journal of the Society for Neuroscience.
2006;26(50):12852-12860.
32. Priest BT, Murphy BA, Lindia JA, Diaz C, Abbadie C, Ritter AM,
Liberator P, Iyer LM, Kash SF, Kohler MG, Kaczorowski GJ, MacIntyre DE, Martin WJ. Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive
behavior. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(26):9382-9387.
33.Tanaka M CT, Ishikawa K, Dib-Hajj SD, Black JA, Waxman SG. SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport. 1998;20;9(6):
967-972.
34. Yen YT, Tu PH, Chen CJ, Lin YW, Hsieh ST, Chen CC. Role of
acid-sensing ion channel 3 in sub-acute-phase inflammation. Molecular
30;256(1):17-20.
43. Joshi SK, Mikusa JP, Hernandez G, Baker S, Shieh CC, Neelands T, Zhang XF, Niforatos W, Kage K, Han P, Krafte D, Faltynek C, Sullivan JP, Jarvis MF, Honore P. Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative , pain states. Pain. 2006;123(1-2):75-82.
44. Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, Nau C, Wood JN, Reeh PW. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature. 2007;447(7146):
855-858.
45. Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A , Kerr BJ, McMahon SB, Boyce S, Hill R, Stanfa LC, Dickenson AH, Wood JN. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci. 1999 Jun;2(6):
541-548.
46. Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, Thomas J, Liu D, Krambis M, Liu Y, McGaraughty S, Chu K, Roeloffs R, Zhong C, Mikusa JP, Hernandez G, Gauvin D, Wade C, Zhu C, Pai M, Scanio M, Shi L, Drizin I, Gregg R, Matulenko M, Hakeem A, Gross M, Johnson M, Marsh K, Wagoner PK, Sullivan JP, Faltynek CR, Krafte DS. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(20):8520-8525.
47. Ekberg J, Jayamanne A, Vaughan CW, Aslan S, Thomas L, Mould J, Drinkwater R, Baker MD, Abrahamsen B, Wood JN, Adams DJ, Christie MJ, Lewis RJ. uO-conotoxin MrVIB selectively blocks Nav1.8
sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(45):17030-17035.
48. Padilla F CM, Coste B, Maingret F, Clerc N, Crest M,Ritter AM, Magloire H, Delmas P:. Expression and localization of the Nav1.9 sodium channel in enteric neurons and in trigeminal sensory endings:
implication for intestinal reflex function and orofacial pain. . Mol Cell Neurosci. 2007;35:138-152.
To investigate the effect of electroacupuncture at Zusanli (ST36) acupoint on expression of sodium channels in mice inflammation pain model
ABSTRACT
Hsiang-Ni Chen1,2 Yi-Wen Lin2
1China Medical University Beigang Hospital
2Graduate Insitute of Acupuncture Science, China Medical University
Key words Electroacupuncture、Inflammation pain、sodium channels 、
Zusanli (ST 36) acupointAim
Voltage-gated sodium channels (Navs）are crucial in modulating neuron excitability especially in nociceptive primary afferent to transduction pain signal. Of all the ten sodium channels, Nav 1.7,Nav 1.8 and Nav 1.9
channels are involved in several pain models. Recent studies have reported that Nav 1.7, Nav 1.8 but not Nav 1.9 can be up-regulated during
carrageenan-induced inflammatory pain in dorsal root ganglia (DRG).
Acupuncture is highly used and known to ameliorate pain sensation by releasing opioid and adenosine. In this study, we examined the curative effect on acupuncture in inflammatory pain and relationship with Nav sodium channels.
Method
We used 18 ICR female mice which divided into control, inflammatory and electroacupuncture groups. Animals receiving electroacupuncture （EA）
15 minutes/day for 4 consecutive days. Then we collected the ipsilateral L3-5 DRGs and analyzed the changes of sodium ion channels.
Result and Conclusion
Our results showed that EA at Zusanli acupoint at 2Hz stimulation reduced mechanical pain from inflammatory pain. Noticeable, the expression of Nav 1.7 and Nav 1.8 were increased at 4 day time and further attenuated by 2Hz EA stimulation. The results can not be observed in Nav 1.9 sodium channels by both immunohistochemistry and Western blot technique in a distinct population of DRG neurons. These results demonstrate that EA at Zusanli reduced carrageenan-induced inflammatory pain by reducing Nav 1.7 and Nav 1.8 overexpression rather than Nav 1.9 in DRGs.