The Korean Journal of Pain

  • 제20권2호
  • /
  • Pages.92-99
  • /
  • 2007
  • /
  • 2005-9159(pISSN)
  • /
  • 2093-0569(eISSN)
대한통증학회 (The Korean Pain Society)
권호 표지
DOI QR코드

DOI QR Code

흰쥐의 술 후 통증 모델에서 T형 칼슘 통로 차단제인 Ethosuximide와 Mibefradil의 항통각과민 효과

Antihyperalgesic Effects of Ethosuximide and Mibefradil, T-type Voltage Activated Calcium Channel Blockers, in a Rat Model of Postoperative Pain

  • 신혜란 (인하대학교 의과대학 마취통증의학교실) ;
  • 차영덕 (인하대학교 의과대학 마취통증의학교실) ;
  • 한정욱 (인하대학교 의과대학 마취통증의학교실) ;
  • 윤정원 (인하대학교 의과대학 마취통증의학교실) ;
  • 김부성 (부천 통증 클리닉) ;
  • 송장호 (인하대학교 의과대학 마취통증의학교실)
  • Shinn, Helen Ki (Department of Anesthesiology and Pain Medicine, College of Medicine, Inha University) ;
  • Cha, Young Deog (Department of Anesthesiology and Pain Medicine, College of Medicine, Inha University) ;
  • Han, Jeong Uk (Department of Anesthesiology and Pain Medicine, College of Medicine, Inha University) ;
  • Yoon, Jeong Won (Department of Anesthesiology and Pain Medicine, College of Medicine, Inha University) ;
  • Kim, Boo Seong (Bucheon Pain Clinic) ;
  • Song, Jang Ho (Department of Anesthesiology and Pain Medicine, College of Medicine, Inha University)
  • 투고 : 2007.07.27
  • 심사 : 2007.09.05
  • 발행 : 2007.12.10
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Background: A correlation between a T-type voltage activated calcium channel (VACC) and pain mechanism has not yet been established. The purpose of this study is to find out the effect of ethosuximide and mibefradil, representative selective T-type VACC blockers on postoperative pain using an incisional pain model of rats. Methods: After performing a plantar incision, rats were stabilized on plastic mesh for 2 hours. Then, the rats were injected with ethosuximide or mibefradil, intraperitoneally and intrathecally. The level of withdrawal threshold to the von Frey filament near the incision site was determined and the dose response curves were obtained. Results: After an intraperitoneal ethosuximide or mibefradil injection, the dose-response curve showed a dose-dependent increase of the threshold in a withdrawal reaction. After an intrathecal injection of ethosuximide, the threshold of a withdrawal reaction to mechanical stimulation increased and the increase was dose-dependent. After an intrathecal injection of mibefradil, no change occurred in either the threshold of a withdrawal reaction to mechanical stimulation or a dose-response curve. Conclusions: The T-type VACC blockers in a rat model of postoperative pain showed the antihyperalgesic effect. This effect might be due to blockade of T-type VACC, which was distributed in the peripheral nociceptors or at the supraspinal level. Further studies of the effect of T-type VACC on a pain transmission mechanism at the spinal cord level would be needed.

키워드

참고문헌

  1. Carbone E, Lux HD: A low voltage-activated, fully inactivating Ca channel in vertebrate sensory neurones. Nature 1984; 310: 501-2 https://doi.org/10.1038/310501a0
  2. Bertolino M, Uinas RR: The central role of voltageactivated and receptor-operated calcium channels in neuronal cells. Annu Rev Phannacol Toxicol 1992; 32: 399-421 https://doi.org/10.1146/annurev.pa.32.040192.002151
  3. Anwyl R: Modulation of venebrate neuronal calcium channels by transmitters. Brain Res Brain Res Rev 1991; 16: 265-81 https://doi.org/10.1016/0165-0173(91)90010-6
  4. Huguenard JR: Low-threshold calcium currents in central nervous system neurons. Annu Rev Physiol 1996; 58: 329-48 https://doi.org/10.1146/annurev.ph.58.030196.001553
  5. Carbone E. Lux AD: A low voltage-activated calcium conductance in embryonic chick sensory neurons. Biophys J 1984; 46: 413-8 https://doi.org/10.1016/S0006-3495(84)84037-0
  6. Chaplan SR, Pogrel JW, Yaksh TL: Role of voltagedependent calcium channel subtypes in experimental tactile allodynia. J Phannacol Exp Ther 1994; 269: 1117-23
  7. Matthews EA, Dickenson AH: Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal hom neuronal responses in a rat model of neuropathy. Pain 2001; 92: 235-46 https://doi.org/10.1016/S0304-3959(01)00255-X
  8. Dogrul A, Gardell LR, Ossipov MH, Tulunay FC, Lai J, Porreca F: Reversal of experimental neuropathic pain by T-type calcium channel blockers. Pain 2003; 105: 159-68 https://doi.org/10.1016/S0304-3959(03)00177-5
  9. Matthews EA, Dickenson AH: Effects of ethosuximide, a T-type $Ca^{2+}$ channel blocker, on dorsal hom neuronal responses in rats. Eur J Phannacol 2001; 415: 141-9 https://doi.org/10.1016/S0014-2999(01)00812-3
  10. Kostyuk PG, Molokanova EA, Pronchuk NF, Savchenko AN. Verkhratsky AN: Different action of ethosuximide on low- and high-threshold calcium currents in rat sensory neurons. Neuroscience 1992; 51: 755-8 https://doi.org/10.1016/0306-4522(92)90515-4
  11. Todorovic SM, Rastogi AJ, Jevtovic-Todorovic V: Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats. Br J Phannacol 2003; 140: 255-60
  12. Shannon HE, Eberle EL, Peters SC: Comparison of the effects of anticonvulsant drugs with diverse mechanisms of action in the formalin test in rats. Neurophannacology 2005; 48: 1012-20 https://doi.org/10.1016/j.neuropharm.2005.01.013
  13. Ertel SI, Enel EA: Low-voltage-activated T-type $Ca^{2+}$ channels. Trends Phannacol Sci 1997; 18: 37-42 https://doi.org/10.1016/S0165-6147(96)01021-8
  14. Jimenez C, Bcurinet E, Leuranguer V, Richard S, Snutch TP, Nargeot 1: Determinants of voltage-dependent inactivation affect mibefradil block of calcium channels. Neuropharmacology 2000; 39: 1-10 https://doi.org/10.1016/S0028-3908(99)00153-7
  15. Hennsmeyer K, Mishra S, Miyagawa K, Minshall R: Physiologic and pathophysiologic relevance of T-type calcium-ion channels: potential indications for Tctype calcium antagonists. Clin Ther 1997; 19(5uppl A): 18-26 https://doi.org/10.1016/S0149-2918(97)80034-3
  16. Lee DS, Goodman S, Dean DM, Lenis J , Ma P, Gervais PB, et al: Randomized comparison of T-type versus L-type calcium-channel blockade on exercise duration in stable angina: results of the posicor reduction of ischemia during exercise (PRIDE) trial. Am Heart J 2002; 144: 60-7 https://doi.org/10.1067/mhj.2002.122869
  17. Banon ME, Eberle EL, Shannon HE: The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil. Eur J Phannacol 2005; 521: 79-85 https://doi.org/10.1016/j.ejphar.2005.08.017
  18. Clozel JP, Ertel EA, Ertel SI: Discovery and main pharmacological properties of mibefradil (Ro 40-5967), the first selective Tvtype calcium channel blocker. J Hypenens Suppl 1997; 15: 17-25
  19. Ertel SI, Clozel JP: Mibefradil (Ro 40-5967): the first selective T-type $Ca^{2+}$ channel blocker. Expert Opin Investing Drugs 1997; 6: 569-82 https://doi.org/10.1517/13543784.6.5.569
  20. Storkson RV, Kjorsvik A, Tjolsen A, Hole K: Lumbar catheterization of the spinal subarachnoid space in the rat. J Neurosei Methods 1996; 65: 167-72 https://doi.org/10.1016/0165-0270(95)00164-6
  21. Brennan TJ, Vandermeulen EP, Gebhan GF: Characterization of a rat model of incisional pain. Pain 1996; 64: 493-501 https://doi.org/10.1016/0304-3959(95)01441-1
  22. Todorovic SM, Meyenburg A. Jevtovic-Todorovic V: Mechanical and thermal aminociccprion in rats following systemic administration of mibcfradil, a Tctype calcium channel blocker. Brain Res 2002; 951: 336-40 https://doi.org/10.1016/S0006-8993(02)03350-4
  23. Flatters SJ, Bennett GJ: Ethosuximide reverses paclitaxeland vincristine-induced painful peripheral neuropathy. Pain 2004; 109: 150-61 https://doi.org/10.1016/j.pain.2004.01.029
  24. Han HC, Lee DH, Chung JM: Characteristics of ectopic discharges in a rat neuropathic pain model. Pain 2000; 84: 253-61 https://doi.org/10.1016/S0304-3959(99)00219-5
  25. Liu X, Eschenfelder S, Blenk KH, lanig W, Habler H: Spontaneous activity ofaxotomized afferent neurons after L5 spinal nerve injury in rats. Pain 2000; 84: 309-18 https://doi.org/10.1016/S0304-3959(99)00211-0
  26. Todorovic SM, Jevtovic-Todorovic V, Meyenburg A, Mennerick S, Perez-Reyes E, Romano C. et al: Redox modulation of T-type calcium channels in rat peripheral nociceptors. Neuron 2001; 31: 75-85 https://doi.org/10.1016/S0896-6273(01)00338-5
  27. White DM, Cousins MJ: Effect of subcutaneous administration of calcium channel blockers on nerve injury-induced hyperalgesia. Brain Res 1998; 801: 50-8 https://doi.org/10.1016/S0006-8993(98)00539-3
  28. Horvath G, Brodacz B, Holzer-Petsche U: Role of calcium channels in the spinal Iransmission of nociceptive information from the mesentery. Pain 2001; 93: 35-41 https://doi.org/10.1016/S0304-3959(01)00290-1
  29. Diaz A, Dickenson AH: Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal hom neurones produced by subcutaneous formalin inflammation. Pain 1997; 69: 93-100 https://doi.org/10.1016/S0304-3959(96)03271-X
  30. Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis RJ: The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain 2002; 96: 119-27 https://doi.org/10.1016/S0304-3959(01)00436-5