Korean J Physiol Pharmacol.  2016 Jul;20(4):407-414. 10.4196/kjpp.2016.20.4.407.

Involvement of spinal muscarinic and serotonergic receptors in the anti-allodynic effect of electroacupuncture in rats with oxaliplatin-induced neuropathic pain

Affiliations
  • 1Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea. skkim77@khu.ac.kr
  • 2Department of East-West Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea.
  • 3Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea.
  • 4Department of Medical Zoology, School of Medicine, Kyung Hee University, Seoul 02447, Korea.

Abstract

This study was performed to investigate whether the spinal cholinergic and serotonergic analgesic systems mediate the relieving effect of electroacupuncture (EA) on oxaliplatin-induced neuropathic cold allodynia in rats. The cold allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) was evaluated by immersing the rat's tail into cold water (4℃) and measuring the withdrawal latency. EA stimulation (2 Hz, 0.3-ms pulse duration, 0.2~0.3 mA) at the acupoint ST36, GV3, or LI11 all showed a significant anti-allodynic effect, which was stronger at ST36. The analgesic effect of EA at ST36 was blocked by intraperitoneal injection of muscarinic acetylcholine receptor antagonist (atropine, 1 mg/kg), but not by nicotinic (mecamylamine, 2 mg/kg) receptor antagonist. Furthermore, intrathecal administration of M(2) (methoctramine, 10 µg) and M(3) (4-DAMP, 10 µg) receptor antagonist, but not M(1) (pirenzepine, 10 µg) receptor antagonist, blocked the effect. Also, spinal administration of 5-HT(3) (MDL-72222, 12 µg) receptor antagonist, but not 5-HT(1A) (NAN-190, 15 µg) or 5-HT(2A) (ketanserin, 30 µg) receptor antagonist, prevented the anti-allodynic effect of EA. These results suggest that EA may have a signifi cant analgesic action against oxaliplatin-induced neuropathic pain, which is mediated by spinal cholinergic (M(2), M(3)) and serotonergic (5-HT(3)) receptors.

Keyword

Acetylcholine; Cold allodynia; Electroacupuncture; Oxaliplatin; Serotonin

MeSH Terms

Acetylcholine
Acupuncture Points
Animals
Electroacupuncture*
Hyperalgesia
Injections, Intraperitoneal
Neuralgia*
Rats*
Receptors, Muscarinic
Serotonin
Tail
Water
Acetylcholine
Receptors, Muscarinic
Serotonin
Water

Figure

  • Fig. 1 Experimental schedule and acupoint specific effect of EA on oxaliplatin-induced cold allodynia.(A) Behavioral tests for cold allodynia were performed before and 20 min after EA treatment in the three groups: (B) LI11 (n=8), (C) GV3 (n=6), and (D) ST36 (n=10). The effect of EA at LI11, GV3 and ST36 significantly increased the TWL. (E) Potency of EA against cold allodynia was significantly greater at GV3 and ST36 comparing with LI11. Data are presented as mean±S.E.M.; ***p<0.001, **p<0.01, *p<0.05; by paired t-test.

  • Fig. 2 Effects of non-selective muscarinic and nicotinic acetylcholine receptor antagonists on EA-induced anti-allodynia.Rats with cold allodynia induced by a single injection of oxaliplatin were randomly divided into three groups. The behavioral tests for cold allodynia were performed before an intraperitoneal injection of antagonists and after EA treatment: (A) NS (n=5), (B) atropine (n=5), and (C) mecamylamine (n=7). The analgesic effect of EA at ST36 was blocked by intraperitoneal injection of atropine (non-selective muscarinic receptor antagonist, 1 mg/kg), but not by intraperitoneal injection of mecamylamine (non-selective nicotinic receptor antagonist, 2 mg/kg). Data are presented as mean±S.E.M.; **p<0.01; by paired t-test.

  • Fig. 3 Effects of spinal muscarinic acetylcholine receptor subtype antagonists on EA-induced anti-allodynia.The behavioral tests for cold allodynia were performed before the intrathecal injection of receptor antagonists and after EA treatment in four groups: (A) NS (n=4), (B) pirenzepine (n=6), (C) methoctramine (n=8), and (D) 4-DAMP (n=7). Methoctramine (M2 receptor antagonist), and 4-DAMP (M3 receptor antagonist) blocked the analgesic effect of EA, whereas, NS and pirenzepine (M1 receptor antagonist) did not block the analgesic effect of EA. Data are presented as mean±S.E.M.; **p<0.01; by paired t-test.

  • Fig. 4 Effect of spinal serotonergic receptor subtypes antagonist on EA-induced anti-allodynia.The behavioral tests for cold allodynia were performed before the intrathecal injection of antagonists and after EA treatment in four groups: (A) DMSO (n=4), (B) NAN-190 (n=6), (C) ketanserin (n=8), and (D) MDL-72222 (n=6). MDL-72222 (5-HT3 receptor antagonist) completely blocked the analgesic effect of EA; however, DMSO, NAN-190 (5-HT1A receptor antagonist), and ketanserin (5-HT2A receptor antagonist) did not alter the anti-allodynic effect of EA. Data are presented as mean±SEM.; ***p<0.001, **p<0.01, *p<0.05; by paired t-test.


Reference

1. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004; 22:23–30. PMID: 14665611.
Article
2. Arany I, Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol. 2003; 23:460–464. PMID: 13680535.
Article
3. Desoize B, Madoulet C. Particular aspects of platinum compounds used at present in cancer treatment. Crit Rev Oncol Hematol. 2002; 42:317–325. PMID: 12050023.
Article
4. Pasetto LM, D'Andrea MR, Rossi E, Monfardini S. Oxaliplatinrelated neurotoxicity: how and why? Crit Rev Oncol Hematol. 2006; 59:159–168. PMID: 16806962.
Article
5. Gamelin E, Gamelin L, Bossi L, Quasthoff S. Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures. Semin Oncol. 2002; 29(5 Suppl 15):21–33. PMID: 12422305.
Article
6. Lehky TJ, Leonard GD, Wilson RH, Grem JL, Floeter MK. Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve. 2004; 29:387–392. PMID: 14981738.
Article
7. Murotani T, Ishizuka T, Nakazawa H, Wang X, Mori K, Sasaki K, Ishida T, Yamatodani A. Possible involvement of histamine, dopamine, and noradrenalin in the periaqueductal gray in electroacupuncture pain relief. Brain Res. 2010; 1306:62–68. PMID: 19819232.
Article
8. Deluze C, Bosia L, Zirbs A, Chantraine A, Vischer TL. Electroacupuncture in fibromyalgia: results of a controlled trial. BMJ. 1992; 305:1249–1252. PMID: 1477566.
Article
9. Kim SK, Park JH, Bae SJ, Kim JH, Hwang BG, Min BI, Park DS, Na HS. Effects of electroacupuncture on cold allodynia in a rat model of neuropathic pain: mediation by spinal adrenergic and serotonergic receptors. Exp Neurol. 2005; 195:430–436. PMID: 16054138.
Article
10. Kim SK, Moon HJ, Park JH, Lee G, Shin MK, Hong MC, Bae H, Jin YH, Min BI. The maintenance of individual differences in the sensitivity of acute and neuropathic pain behaviors to electroacupuncture in rats. Brain Res Bull. 2007; 74:357–360. PMID: 17845910.
Article
11. Park JH, Han JB, Kim SK, Park JH, Go DH, Sun B, Min BI. Spinal GABA receptors mediate the suppressive effect of electroacupuncture on cold allodynia in rats. Brain Res. 2010; 1322:24–29. PMID: 20138846.
Article
12. Bao T, Zhang R, Badros A, Lao L. Acupuncture treatment for bortezomib-induced peripheral neuropathy: a case report. Pain Res Treat. 2011; 2011:920807. PMID: 22110934.
Article
13. Donald GK, Tobin I, Stringer J. Evaluation of acupuncture in the management of chemotherapy-induced peripheral neuropathy. Acupunct Med. 2011; 29:230–233. PMID: 21875929.
Article
14. Park JH, Kim SK, Kim HN, Sun B, Koo S, Choi SM, Bae H, Min BI. Spinal cholinergic mechanism of the relieving effects of electroacupuncture on cold and warm allodynia in a rat model of neuropathic pain. J Physiol Sci. 2009; 59:291–298. PMID: 19343482.
Article
15. Kim W, Kim SK, Min BI. Mechanisms of electroacupuncture-induced analgesia on neuropathic pain in animal model. Evid Based Complement Alternat Med. 2013; 2013:436913. PMID: 23983779.
Article
16. Moon HJ, Lim BS, Lee DI, Ye MS, Lee G, Min BI, Bae H, Na HS, Kim SK. Effects of electroacupuncture on oxaliplatin-induced neuropathic cold hypersensitivity in rats. J Physiol Sci. 2014; 64:151–156. PMID: 24158835.
Article
17. Bartolini A, Di Cesare Mannelli L, Ghelardini C. Analgesic and antineuropathic drugs acting through central cholinergic mechanisms. Recent Pat CNS Drug Discov. 2011; 6:119–140. PMID: 21585331.
Article
18. Wang JY, Meng FY, Chen SP, Gao YH, Liu JL. Analysis on interrelation between electroacupuncture-induced cumulative analgesic effect and hypothalamic cholinergic activities in chronic neuropathic pain rats. Chin J Integr Med. 2012; 18:699–707. PMID: 22936324.
Article
19. Eisenach JC. Muscarinic-mediated analgesia. Life Sci. 1999; 64:549–554. PMID: 10069522.
Article
20. Millan MJ. Descending control of pain. Prog Neurobiol. 2002; 66:355–474. PMID: 12034378.
Article
21. Takeda D, Nakatsuka T, Gu JG, Yoshida M. The activation of nicotinic acetylcholine receptors enhances the inhibitory synaptic transmission in the deep dorsal horn neurons of the adult rat spinal cord. Mol Pain. 2007; 3:26. PMID: 17894865.
Article
22. Bardin L. The complex role of serotonin and 5-HT receptors in chronic pain. Behav Pharmacol. 2011; 22:390–404. PMID: 21808193.
Article
23. Xie DJ, Uta D, Feng PY, Wakita M, Shin MC, Furue H, Yoshimura M. Identification of 5-HT receptor subtypes enhancing inhibitory transmission in the rat spinal dorsal horn in vitro. Mol Pain. 2012; 8:58. PMID: 22906126.
Article
24. Jeong HJ, Mitchell VA, Vaughan CW. Role of 5-HT1 receptor subtypes in the modulation of pain and synaptic transmission in rat spinal superficial dorsal horn. Br J Pharmacol. 2012; 165:1956–1965. PMID: 21950560.
25. Radhakrishnan R, King EW, Dickman JK, Herold CA, Johnston NF, Spurgin ML, Sluka KA. Spinal 5-HT2 and 5-HT3 receptors mediate low, but not high, frequency TENS-induced antihyperalgesia in rats. Pain. 2003; 105:205–213. PMID: 14499437.
26. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983; 16:109–110. PMID: 6877845.
Article
27. Ling B, Coudoré F, Decalonne L, Eschalier A, Authier N. Comparative antiallodynic activity of morphine, pregabalin and lidocaine in a rat model of neuropathic pain produced by one oxaliplatin injection. Neuropharmacology. 2008; 55:724–728. PMID: 18598708.
Article
28. Yin CS, Jeong HS, Park HJ, Baik Y, Yoon MH, Choi CB, Koh HG. A proposed transpositional acupoint system in a mouse and rat model. Res Vet Sci. 2008; 84:159–165. PMID: 17559895.
Article
29. Mestre C, Pélissier T, Fialip J, Wilcox G, Eschalier A. A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Methods. 1994; 32:197–200. PMID: 7881133.
Article
30. De la Calle JL, Paíno CL. A procedure for direct lumbar puncture in rats. Brain Res Bull. 2002; 59:245–250. PMID: 12431755.
Article
31. Hagiwara S, Iwasaka H, Takeshima N, Noguchi T. Mechanisms of analgesic action of pulsed radiofrequency on adjuvant-induced pain in the rat: roles of descending adrenergic and serotonergic systems. Eur J Pain. 2009; 13:249–252. PMID: 18539061.
Article
32. Lee JH, Li DX, Yoon H, Go D, Quan FS, Min BI, Kim SK. Serotonergic mechanism of the relieving effect of bee venom acupuncture on oxaliplatin-induced neuropathic cold allodynia in rats. BMC Complement Altern Med. 2014; 14:471. PMID: 25481535.
Article
33. Yoon H, Kim MJ, Yoon I, Li DX, Bae H, Kim SK. Nicotinic acetylcholine receptors mediate the suppressive effect of an injection of diluted bee venom into the GV3 acupoint on oxaliplatin-induced neuropathic cold allodynia in rats. Biol Pharm Bull. 2015; 38:710–714. PMID: 25752933.
Article
34. Ormseth MJ, Scholz BA, Boomershine CS. Duloxetine in the management of diabetic peripheral neuropathic pain. Patient Prefer Adherence. 2011; 5:343–356. PMID: 21845034.
35. Serpell MG. Neuropathic pain study group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002; 99:557–566. PMID: 12406532.
Article
36. Lin JG, Lo MW, Wen YR, Hsieh CL, Tsai SK, Sun WZ. The effect of high and low frequency electroacupuncture in pain after lower abdominal surgery. Pain. 2002; 99:509–514. PMID: 12406527.
Article
37. Kim JH, Min BI, Na HS, Park DS. Relieving effects of electroacupuncture on mechanical allodynia in neuropathic pain model of inferior caudal trunk injury in rat: mediation by spinal opioid receptors. Brain Res. 2004; 998:230–236. PMID: 14751594.
Article
38. Höglund AU, Baghdoyan HA. M2, M3 and M4, but not M1, muscarinic receptor subtypes are present in rat spinal cord. J Pharmacol Exp Ther. 1997; 281:470–477. PMID: 9103533.
39. Reimann W, Schlütz H, Selve N. The antinociceptive effects of morphine, desipramine, and serotonin and their combinations after intrathecal injection in the rat. Anesth Analg. 1999; 88:141–145. PMID: 9895081.
Article
40. Yaksh TL, Tyce GM. Microinjection of morphine into the periaqueductal gray evokes the release of serotonin from spinal cord. Brain Res. 1979; 171:176–181. PMID: 466437.
Article
41. Dirksen R, Nijhuis GM. The relevance of cholinergic transmission at the spinal level to opiate effectiveness. Eur J Pharmacol. 1983; 91:215–221. PMID: 6617742.
Article
42. Chen SR, Pan HL. Spinal endogenous acetylcholine contributes to the analgesic effect of systemic morphine in rats. Anesthesiology. 2001; 95:525–530. PMID: 11506129.
Article
43. Lim BS, Moon HJ, Li DX, Gil M, Min JK, Lee G, Bae H, Kim SK, Min BI. Effect of bee venom acupuncture on oxaliplatin-induced cold allodynia in rats. Evid Based Complement Alternat Med. 2013; 2013:369324. PMID: 24058370.
Article
44. Roh DH, Kwon YB, Kim HW, Ham TW, Yoon SY, Kang SY, Han HJ, Lee HJ, Beitz AJ, Lee JH. Acupoint stimulation with diluted bee venom (apipuncture) alleviates thermal hyperalgesia in a rodent neuropathic pain model: involvement of spinal alpha 2-adrenoceptors. J Pain. 2004; 5:297–303. PMID: 15336634.
45. Kim HN, Park JH, Kim SK, Sun B, Koo S, Choi SM, Bae H, Min BI. Electroacupuncture potentiates the antiallodynic effect of intrathecal neostigmine in a rat model of neuropathic pain. J Physiol Sci. 2008; 58:357–360. PMID: 18840324.
Article
Full Text Links
  • KJPP
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr