一种新型N-型电压敏感性钙通道拮抗剂虎纹蜘蛛毒素-I对大鼠内脏痛模型镇痛作用的研究

南方医科大学学报 ›› 2005, Vol. 25 ›› Issue (01): 10-14.

一种新型N-型电压敏感性钙通道拮抗剂虎纹蜘蛛毒素-I对大鼠内脏痛模型镇痛作用的研究

陈嘉勤¹, 陈威华¹, 邓梅春², 黎冠², 康园¹, 丁振华³, 梁宋平²

1. 湖南师范大学体育学院, 湖南长沙410081;
2. 湖南师范大学生命科学院, 湖南长沙410081;
3. 南方医科大学热卫系, 广东广州510515

出版日期:2005-01-20 发布日期:2005-01-20
基金资助:
收稿日期:2004-8-10。
基金项目:国家自然科学基金(39370152);国家“863”计划资助项目(103-13-01-06)
作者简介:陈嘉勤,女,1988年毕业于暨南大学医学院,医学硕士,现为湖南师范大学体育学院教授,主要从事镇痛活性多肽的药效、药理和毒理学研究
通讯作者:梁宋平,电话:0731-8872556,E-mail:liangsp@public.cs.hn.cn

Analgesic effect of huwentoxin-I, a new N-type voltage-sensitive calcium channel blocker, on acute visceral pain in rats

CHEN Jia-qin¹, CHEN Wei-hua¹, DENG Mei-chun², LI Guan², KANG Yuan¹, DING Zhen-hua³, LIANG Song-ping²

1. 湖南师范大学体育学院, 湖南长沙410081;
2. 湖南师范大学生命科学院, 湖南长沙410081;
3. 南方医科大学热卫系, 广东广州510515

Online:2005-01-20 Published:2005-01-20

摘要/Abstract

摘要： 目的研究一种新型N-型电压敏感性钙通道拮抗剂虎纹蜘蛛毒素-I(HWAP-I)经蛛网膜下腔用药对福尔马林诱导的大鼠急性炎性内脏疼痛的抑制作用。方法福尔马林快速注入SD大鼠乙状结肠壁粘膜下层作为疼痛模型,以数种可评估的反映内脏疼痛的固定性行为作为疼痛评分指标(疼痛分数)。此前30min经留置的导管注射各待测试剂于蛛网膜下腔内,以观察其对该模型疼痛行为的作用。结果以生理盐水阴性对照组和美国同类镇痛新药SNX-111(0.2,0.5和0.75μg/kg·b.w.)和盐酸吗啡(0.05,0.1和0.2μg/kg·b.w.)两个阳性对照组比较,HWAP-I(0.1~1.0μg/kg·b.w.)均能以剂量依赖方式明显抑制福尔马林结肠壁粘膜下注射所诱导的大鼠急性伤害性行为反应。HWAP-I和SNX-111在0.2μg/kg·b.w.时即有稳定和明显的疼痛抑制作用。虽然在同等剂量时SNX-111镇痛效果略大于HWAP-I,但在≥0.5μg/kg·b.w.的较高剂量时SNX-111会引起大鼠产生明显的运动能力障碍,而HWAP-I在此剂量范围内则未见明显的这类毒副作用。盐酸吗啡镇痛作用起效快于HWAP-I和SNX-111,但维持时间较后二者短。结论作为一种新型的多肽类N-型电压敏感性钙通道拮抗剂,HWAP-I和其类似物SNX-111经蛛网膜下腔用药后,对结肠壁粘膜下注射福尔马林引起的大鼠急性炎性内脏疼痛具有和盐酸吗啡类似的,剂量依赖性抑制作用,且维持时间更长。

Abstract: Objective To study the antinociceptive effect of intrathecally administered huwentoxin-I (HWTX-I or HWAP-I) on visceral pain in rats with acute colon inflammation. Methods Nociceptive behaviors was induced by formalin injected into the submucosa of the sigmoid colon in rats and the typical behavioral patterns induced served as the indexes for visceral nociception scoring. HWAP-I (0.1-1.0 μg/kg·b.w.), SNX-111 (0.2, 0.5 and 0.75 μg/kg·b.w.) and morphine hydrochloride (0.05, 0.1 and 0.2 μg/kg·b.w.) were administered subarachnoidally 30 min before formalin injection. Results Similar to SNX-111 and hydrochloride morphine, HWAP-I administered subarachnoidally significantly reduced nociceptive responses in a dose-dependent manner in the rat model of visceral pain (P<0.05). Both HWAP-I and SNX-111produced pain suppression effect at the dosage of 0.2 μg/kg·b.w., and in spite of the stronger antinociceptive effect of SNX-111 than HWAP-I at the same doses, SNX-111 caused obvious motor dysfunction in the rats at the doses higher than 0.5 μg/kg·b.w., which was not observed with HWAP-1 at such doses. The antinociceptive effect of morphine hydrochloride was initiated faster but lasted for a shorter period of time than the effects of HWAP-I and SNX-111. Conclusion As a potent blocker of neuronal N-type voltage-sensitive calcium channel, HWAP-I induces remarkably dose-dependent inhibitory effect similar to SNX-111 and morphine on visceral pain induced by sigmoid colon submucosal injection of formalin in conscious rats.

中图分类号:

R971

陈嘉勤¹, 陈威华¹, 邓梅春², 黎冠², 康园¹, 丁振华³, 梁宋平². 一种新型N-型电压敏感性钙通道拮抗剂虎纹蜘蛛毒素-I对大鼠内脏痛模型镇痛作用的研究[J]. 南方医科大学学报, 2005, 25(01): 10-14.

CHEN Jia-qin¹, CHEN Wei-hua¹, DENG Mei-chun², LI Guan², KANG Yuan¹, DING Zhen-hua³, LIANG Song-ping². Analgesic effect of huwentoxin-I, a new N-type voltage-sensitive calcium channel blocker, on acute visceral pain in rats[J]. Journal of Southern Medical University, 2005, 25(01): 10-14.

参考文献

[1] Wang JF, Peng X J, Xie LP. A new species of genus Ornithoctonus fromsouthChina[J]. Acta SciNatl Univ Norm Hunan, 1993,16:51-4.
[2] Liang SP, Zhang DY, Pan X, et al. Properties and amino acid sequence of Huwentoxin-1, a neurotoxin purified from the venom of the Chinese bird spider Ornithoctonus Huwena[J]. Toxicon, 1993,31(8): 969-78.
[3] Penk K, Chen XD, Liang SP. The effect of Huwen toxin-1 on channels in differential NG108-15 cells, a patch-clamp study [J]. Toxicon, 2001, 39(4): 491-8.
[4] Augustine GJ, Charlton MP, Smith SJ. Calcium action in synaptic transmitter release[J]. Annu Rev Neurosci, 1987, 10: 633-93.
[5] Kato T, Ozaki T, Tamura K, et al. Novel calcium antagonists with both calcium overload inhibition and antioxidant activity. 1. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(aminopropyl)thiazolidinones [J]. J Med Chem, 1998, 41(22): 4309-16.
[6] Porzig H. Pharmacological modulation of voltage-dependent calcium channels in intact cells [J]. Rev Physiol Biochem Pharmacol,1990, 114: 209-62.
[7] Aosaki T, Kasai H. Characterization of two kinds of high-voltage-activated Ca-channel currents in chick sensory neurons. Differential sensitivity to dihydropyridines and omega-conotoxin GVIA [J].Pflugers Arch, 1989, 414(2): 150-6.
[8] Kohno T, Kim JI, Kobayashi K. Three-dimensional structure in solution of the calcium channel blocker omega-conotoxin MVIIA [J].Biochemistry, 1995, 34(32): 10256-65.
[9] Bowersox SS, Gadbois T, Singh T, et al. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain[J]. J Pharmacol Exp Ther, 1996, 279: 1243-9.
[10] Brose WG, Gutlove DP, Luther RR, et al. Use of intrathecal SNX-111,a novel, N-type, voltage-sensitive, calcium channel blocker, in themanagement of intractable brachial plexus avulsion pain [J]. Clin J Pain, 1997, 13(3): 256-9.
[11] Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial[J]. JAMA, 2004, 291(1): 63-70.
[12] Yaksh TL, Rndy TA. Chronic catheterization of the spinal subarachnoid space[J]. Physiol behav, 1976, 17(6): 1031-6.
[13] Miampamba M, Chery-Croge S, Gorry F, et al. Inflammation of the colonic wall induced by formalin as a model of acute visceral pain [J]. Pain, 1994, 57(3): 327-34.
[14] Abeli L, Cotue B, Somme V, et al. A method for studying pain arising from the urinary bladder in conscious freely-movingrats [J]. J Urol, 1989, 141(1): 148-51.
[15] Staats PS, Yearwood T, Charapata SG. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial[J]. JAMA, 2004, 291(1): 63-70.
[16] Jain KK. An evaluation of intrathecal ziconotide for the treatment of chronic pain [J]. Expert Opin Investig Drugs, 2000, 9(10): 2403-10.