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백서의 척수신경결찰모델에서 Morphine의 투여가 항이질통 효과와 척수 α2 아드레날린계 수용체 아형 mRNA 발현에 미치는 영향

The Antiallodynic Effect and the Change of the α2 Adrenergic Receptor Subtype mRNA Expression by Morphine Administration in a Spinal Nerve Ligation Rat Model

  • 정규연 (부산대학교 의학전문대학원 마취통증의학교실) ;
  • 신상욱 (부산대학교 의학전문대학원 마취통증의학교실) ;
  • 권수아 (부산대학교 의학전문대학원 마취통증의학교실) ;
  • 김태균 (부산대학교 의학전문대학원 마취통증의학교실) ;
  • 백승훈 (부산대학교 의학전문대학원 마취통증의학교실) ;
  • 백승완 (부산대학교 의학전문대학원 마취통증의학교실)
  • Chung, Kyu Yeon (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Shin, Sang Wook (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Kwon, Su Ah (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Kim, Tae Kyun (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Baek, Seung Hoon (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University) ;
  • Baik, Seong Wan (Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University)
  • 투고 : 2009.02.03
  • 심사 : 2009.03.25
  • 발행 : 2009.04.01

초록

Background: The neuropathic pain arising from nerve injury is difficult to treat and the therapeutic effects of opioid drugs remain debatable. Agonists acting at the ${\alpha}_2$ adrenergic and opioid receptors have analgesic properties and they act synergistically when co-administered in the spinal cord. The lack of subtype-selective pharmacological agents has previously impeded the synergistic effects that are mediated by the adrenergic receptor subtypes. Methods: We created neuropathic pain model by ligating the L5 spinal nerve in Sprague-Dawley rats (n = 18). We divided the rats into three groups (n = 6 for each group), and we administered intraperitoneal morphine (1 mg/kg, 3 mg/kg, 5 mg/kg) and then we measured the mechanical allodynia with using von-Frey filaments for 8 hours. We then injected morphine (5 mg/kg) intraperitoneally, twice a day for 2 weeks. We measured the tactile and cold allodynia in the morphine group (n = 9) and the saline group (n = 9). After 2 weeks, we decapitated the rats and harvested the spinal cords at the level of lumbar enlargement. We compared the ${\alpha}_2$ subtype mRNA expression with that of control group (n = 6) by performing real time polymerase chain reaction (RTPCR). Results: Intraperitoneal morphine reduced the neuropathic pain behavior in the dose-dependent manner. Chronic morphine administration showed an antiallodynic effect on the neuropathic pain rat model. The rats did not display tolerance or hyperalgesia. The expression of the mRNAs of the ${\alpha}_{2A}$, ${\alpha}_{2B}$, ${\alpha}_{2C}$ subtypes decreased, and morphine attenuated this effect. But we could not get statistically proven results. Conclusions: Systemic administration of morphine can attenuate allodynia during both the short-term and long-term time course. Morphine has an influence on the expression of ${\alpha}_2$ receptor subtype mRNA. Yet we need more research to determine the precise effect of morphine on the ${\alpha}_2$ subtype gene expression.

키워드

과제정보

연구 과제 주관 기관 : 부산대학교

참고문헌

  1. Suzuki R, Chapman V, Dickenson AH: The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain. Pain 1999; 80: 215-28 https://doi.org/10.1016/S0304-3959(98)00208-5
  2. Kim SK, Min BI, Kim JH, Hwang BG, Yoo GY, Park DS, et al: Effects of alpha1- and alpha2-adrenoreceptor antagonists on cold allodynia in a rat tail model of neuropathic pain. Brain Res 2005; 1039: 207-10 https://doi.org/10.1016/j.brainres.2005.01.051
  3. Aantaa R, Marjam$\ddot{a}$ki A, Scheinin M: Molecular pharmacology of alpha 2-adrenoceptor subtypes. Ann Med 1995;27: 439-49 https://doi.org/10.3109/07853899509002452
  4. Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL: The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy. J Neurosci 1997; 17:7157-65
  5. Stone LS, Kitto KF, Eisenach JC, Fairbanks CA, Wilcox GL: ST91 [2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride]-mediated spinal antinociception and synergy with opioids persists in the absence of functional alpha-2A- or alpha-2C-adrenergic receptors. J Pharmacol Exp Ther 2007; 323: 899-906 https://doi.org/10.1124/jpet.107.125526
  6. Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 355-63 https://doi.org/10.1016/0304-3959(92)90041-9
  7. Han DW, Kweon TD, Lee JS, Lee YW: Antiallodynic effect of pregabalin in rat models of sympathetically maintained and sympathetic independent neuropathic pain. Yonsei Med J 2007; 48: 41-47 https://doi.org/10.3349/ymj.2007.48.1.41
  8. Kim TW, Shin CS, Kim CH, Shin SW: Tramadol, alpha-2 adrenalin receptor subtype and neuropathic rat model. Korean J Anesthesiol 2007; 52: 328-34 https://doi.org/10.4097/kjae.2007.52.3.328
  9. Duflo F, Li X, Bantel C, Pancaro C, Vincler M, Eisenach JC: Peripheral nerve injury alters the alpha2 adrenoceptor subtype activated by clonidine for analgesia. Anesthesiology 2002; 97: 636-41 https://doi.org/10.1097/00000542-200209000-00018
  10. Zhao C, Tall JM, Meyer RA, Raja SN: Antiallodynic effects of systemic and intrathecal morphine in the spared nerve injury model of neuropathic pain in rats. Anesthesiology 2004; 100: 905-11 https://doi.org/10.1097/00000542-200404000-00021
  11. Besse D, Lombard MC, Perrot S, Besson JM: Regulation of opioid binding sites in the superficial dorsal horn of the rat spinal cord following loose ligation of the sciatic nerve:Comparison with sciatic nerve section and lumbar dorsal rhizotomy. Neuroscience 1992; 50: 921-33 https://doi.org/10.1016/0306-4522(92)90215-N
  12. Goff JR, Burkey AR, Goff DJ, Jasmin L: Reorganization of the spinal dorsal horn in models of chronic pain: correlation with behaviour. Neuroscience 1998; 82: 559-74 https://doi.org/10.1016/S0306-4522(97)00298-4
  13. Yu W, Hao JX, Xu XJ, Wiesenfeld-Hallin Z: Comparison of the anti-allodynic and antinociceptive effects of systemic;intrathecal and intracerebroventricular morphine in a rat model of central neuropathic pain. Eur J Pain 1997; 1:17-29 https://doi.org/10.1016/S1090-3801(97)90049-5
  14. Bian D, Nichols ML, Ossipov MH, Lai J, Porreca F: Characterization of the antiallodynic efficacy of morphine in a model of neuropathic pain in rats. Neuroreport 1995;6: 1981-4 https://doi.org/10.1097/00001756-199510010-00007
  15. Przewlocka B, Mika J, Labuz D, Toth G, Przewlocki R: Spinal analgesic action of endomorphins in acute, inflammatory and neuropathic pain in rats. Eur J Pharmacol 1999;367: 189-96 https://doi.org/10.1016/S0014-2999(98)00956-X
  16. Zollner C, Mousa SA, Fischer O, Rittner HL, Shaqura M, Brack A, et al: Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. J Clin Invest 2008; 118: 1065-73
  17. Woolf CJ, Costigan M: Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci USA 1999; 96: 7723-30 https://doi.org/10.1073/pnas.96.14.7723
  18. Chung KY, Shin SW, Choi BS, Kim CH, Kim KH, Kim HK: Spinal alpha2 adrenoceptor and antiallodynic effect by clonidine after chronic administration of 4-methylcatechol in neuropathic rat pain model. Korean J Pain 2008; 21: 179-86 https://doi.org/10.3344/kjp.2008.21.3.179
  19. Stone LS, Vulchanova L, Riedl MS, Wang J, Williams FG, Wilcox GL, et al: Effects of peripheral nerve injury on alpha-2A and alpha-2C adrenergic receptor immunoreactivity in the rat spinal cord. Neuroscience 1999; 93: 1399-407 https://doi.org/10.1016/S0306-4522(99)00209-2
  20. Wei H, Pertovaara A: Spinal and pontine alpha2-adrenoceptors have opposite effects on pain-related behavior in the neuropathic rat. Eur J Pharmacol 2006; 551: 41-9 https://doi.org/10.1016/j.ejphar.2006.08.064
  21. Nicholas AP, Pieribone V, H$\ddot{o}$kfelt T: Distributions of mRNAs for alpha-2 adrenergic receptor subtypes in rat brain: An in situ hybridization study. J Comp Neurol 1993;328: 575-94 https://doi.org/10.1002/cne.903280409
  22. Leiphart JW, Dills CV, Levy RM: Decreased spinal alpha2a- and alpha2c-adrenergic receptor subtype mRNA in a rat model of neuropathic pain. Neurosci Lett 2003; 349:5-8 https://doi.org/10.1016/S0304-3940(03)00610-4
  23. Shi TS, Winzer-Serhan U, Leslie F, H$\ddot{o}$kfelt T: Distribution and regulation of alpha(2)-adrenoceptors in rat dorsal root ganglia. Pain 2000; 84: 319-30 https://doi.org/10.1016/S0304-3959(99)00224-9
  24. Shi TJ, Winzer-Serhan U, Leslie F, Hokfelt T: Distribution of alpha2-adrenoceptor mRNAs in the rat lumbar spinal cord in normal and axotomized rats. Neuroreport 1999; 10:2835-9 https://doi.org/10.1097/00001756-199909090-00025
  25. Ongioco RR, Richardson CD, Rudner XL, Stafford-Smith M, Schwinn DA: Alpha2-adrenergic receptors in human dorsal root ganglia: Predominance of alpha2b and alpha2c subtype mRNAs. Anesthesiology 2000; 92: 968-76 https://doi.org/10.1097/00000542-200004000-00013
  26. Chen YP, Chen SR, Pan HL: Effect of morphine on deep dorsal horn projection neurons depends on spinal GABAergic and glycinergic tone: implications for reduced opioid effect in neuropathic pain. J Pharmacol Exp Ther 2005; 315:696-703 https://doi.org/10.1124/jpet.105.091314