The Korean Journal of Pain

  • 제22권1호
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  • Pages.16-20
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  • 2009
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  • 2005-9159(pISSN)
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  • 2093-0569(eISSN)
대한통증학회 (The Korean Pain Society)
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좌골신경 만성협착손상 흰쥐에서 척수강 내로 투여된 Zaprinast의 항이질통 효과

The Antiallodynic Effects of Intrathecal Zaprinast in Rats with Chronic Constriction Injury of the Sciatic Nerve

  • 이재도 (울산대학교 의과대학 서울아산병원 마취통증의학교실) ;
  • 전인구 (울산대학교 의과대학 서울아산병원 마취통증의학교실) ;
  • 최윤식 (울산대학교 의과대학 서울아산병원 마취통증의학교실) ;
  • 임소현 (울산대학교 의과대학 서울아산병원 마취통증의학교실) ;
  • 박종연 (울산대학교 의과대학 서울아산병원 마취통증의학교실)
  • Lee, Jae Do (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Jun, In Gu (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Yun Sik (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Im, So Hyun (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Park, Jong Yeon (Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine)
  • 투고 : 2009.02.04
  • 심사 : 2009.04.06
  • 발행 : 2009.04.01
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초록

Background: Zaprinast is an inhibitor of phosphodiesterase 5, 6 and 9. Phosphodiesterase inhibitors could produce anti-nociceptive effects by promoting the accumulation of cGMP. We hypothesized that intrathecal zaprinast could attenuate the allodynia induced by chronic constriction injury of the sciatic nerve in rat. Methods: Sprague-Dawley rats were prepared with four loose ligations of the left sciatic nerve just proximal to the trifurcation into the sural, peroneal and tibial nerve branches. Tactile allodynia was measured by applying von Frey filaments to the lesioned hindpaw. The thresholds for the withdrawal responses were assessed. Zaprinast ($3-100{\mu}g$) was administered intrathecally by the direct lumbar puncture method to obtain the dose-response curve and the 50% effective dose ($ED_{50}$). Measurements were taken before and 15, 30, 45, 60, 90, 120, and 180 min after the intrathecal doses of zaprinast. The side effects were also observed. Results: Intrathecal zaprinast resulted in a dose-dependent antiallodynic effect. The maximal effects occurred within 15-30 min and then they gradually decreased down to the baseline level over time in all the groups. There was a dose dependent increase in the magnitude and duration of the effect. The $ED_{50}$ value was $17.4{\mu}g$ (95% confidence intervals; $14.7-20.5{\mu}g$). No severe motor weakness or sedation was observed in any of the rats. Conclusions: Intrathecally administered zaprinast produced a dose-dependent antiallodynic effect in the chronic constriction injury neuropathic pain model. These findings suggest that spinal phosphodiesterase 5, 6 and 9 may play an important role in the modulation of neuropathic pain.

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과제정보

연구 과제 주관 기관 : 아산생명과학연구소

참고문헌

  1. 1. Zimmermann M: Pathobiology of neuropathic pain. Eur J Pharmacol 2001; 429: 23-37 https://doi.org/10.1016/S0014-2999(01)01303-6
  2. Attal N, Jazat F, Kayser V, Guilbaud G: Further evidence for 'pain-related' behaviours in a model of unilateral peripheral mononeuropathy. Pain 1990; 41: 235-51 https://doi.org/10.1016/0304-3959(90)90022-6
  3. Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33: 87-107 https://doi.org/10.1016/0304-3959(88)90209-6
  4. Kupers RC, Nuytten D, De Castro-Costa M, Gybels JM: A time course analysis of the changes in spontaneous and evoked behaviour in a rat model of neuropathic pain. Pain 1992; 50: 101-11 https://doi.org/10.1016/0304-3959(92)90117-T
  5. Jain NK, Patil CS, Singh A, Kulkarni SK: Sildenafilinduced peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Brain Res 2001; 909: 170-8 https://doi.org/10.1016/S0006-8993(01)02673-7
  6. Patil CS, Padi SV, Singh VP, Kulkarni SK: Sildenafil induces hyperalgesia via activation of the NO-cGMP pathway in the rat neuropathic pain model. Inflammopharmacology 2006; 14: 22-7 https://doi.org/10.1007/s10787-006-1511-y
  7. Hoheisel U, Unger T, Mense S: The possible role of the NO-cGMP pathway in nociception: different spinal and supraspinal action of enzyme blockers on rat dorsal horn neurones. Pain 2005; 117: 358-67 https://doi.org/10.1016/j.pain.2005.06.023
  8. Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, et al: Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 2000; 52: 375-414
  9. Park SK, Kim CM, Jeong ST, Kim SJ, Shin DJ, Bae HB, et al: Effect of zaprinast, a phosphodiesterse inhibitor, on formalin-induced nociception and hemodynamics in the rat spinal cord. Korean J Anesthesiol 2005; 48: 651-5 https://doi.org/10.4097/kjae.2005.48.6.651
  10. Xu JJ, Walla BC, Diaz MF, Fuller GN, Gutstein HB:Intermittent lumbar puncture in rats: a novel method for the experimental study of opioid tolerance. Anesth Analg 2006;103: 714-20 https://doi.org/10.1213/01.ane.0000226100.46866.ea
  11. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL:Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55-63 https://doi.org/10.1016/0165-0270(94)90144-9
  12. Tallarida RJ, Porreca F, Cowan A: Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci 1989; 45: 947-61 https://doi.org/10.1016/0024-3205(89)90148-3
  13. Beavo JA, Reifsnyder DH: Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci 1990; 11: 150-5 https://doi.org/10.1016/0165-6147(90)90066-H
  14. Amarante LH, Duarte ID: The kappa-opioid agonist (＋/ −)-bremazocine elicits eripheral antinociception by activation of the L-arginine/nitric oxide/cyclic GMP pathway. Eur J Pharmacol 2002; 454: 19-23 https://doi.org/10.1016/S0014-2999(02)02275-6
  15. Uckert S, Hedlund P, Andersson KE, Truss MC, Jonas U, Stief CG: Update on phosphodiesterase (PDE) isoenzymes as pharmacologic targets in urology: present and future. Eur Urol 2006; 50: 1194-207 https://doi.org/10.1016/j.eururo.2006.05.025
  16. Moreland RB, Goldstein II, Kim NN, Traish A: Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor. Trends Endocrinol Metab 1999; 10: 97-104 https://doi.org/10.1016/S1043-2760(98)00127-1
  17. Pyne NJ, Arshavsky V, Lochhead A: cGMP signal termination. Biochem Soc Trans 1996; 24: 1019-22 https://doi.org/10.1042/bst0241019
  18. Sousa AM, Prado WA: The dual effect of a nitric oxide donor in nociception. Brain Res 2001; 897: 9-19 https://doi.org/10.1016/S0006-8993(01)01995-3
  19. Tegeder I, Schmidtko A, Niederberger E, Ruth P, Geisslinger G: Dual effects of spinally delivered 8-bromo-cyclic guanosine mono-phosphate (8-bromo-cGMP) in formalininduced nociception in rats. Neurosci Lett 2002; 332: 146-50 https://doi.org/10.1016/S0304-3940(02)00938-2