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浙江大学学报（医学版） 2011年第2期40卷 217-221,229页

作者：寿雯婷张世红陈忠卫生部医学神经生物学重点实验室浙江大学医学院药理学系浙江杭州310058

多种钠离子通道亚型在初级感觉神经元中的表达及动态调节,影响神经病理性疼痛的发生、发展及维持过程。SCN9A基因(编码Nav1.7)的多个位点突变被认为与人类多种可遗传的疼痛疾病密切相关。转基因技术和特异性敲除技术的应用发现,Nav1.3、... 详细信息

多种钠离子通道亚型在初级感觉神经元中的表达及动态调节,影响神经病理性疼痛的发生、发展及维持过程。SCN9A基因(编码Nav1.7)的多个位点突变被认为与人类多种可遗传的疼痛疾病密切相关。转基因技术和特异性敲除技术的应用发现,Nav1.3、Nav1.8和Nav1.9在神经病理性疼痛的发生和维持方面起到重要的作用。因此,研究电压依赖性钠离子通道在神经病理性疼痛中的作用,有利于揭示该种疾病的发生和维持机制,也可为开发新一代镇痛药物提供理论依据。

关键词：钠通道/代谢钠通道/遗传学神经痛/病理生理学神经病理性疼痛电压依赖的钠离子通道 Nav1.7 Nav1.8

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Wind-up of spinal cord neurones and pain sensation: much ado about something?

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PROGRESS IN NEUROBIOLOGY 2000年第2期61卷 169-203页

作者： Herrero, JF Laird, JMA Lopez-Garcia, JA Univ Alcala de Henares Dept Fisiol Madrid 28871 Spain

Wind-up is a frequency-dependent increase in the excitability of spinal cord neurones, evoked by electrical stimulation of afferent C-fibres. Although it has been studied over the past thirty years, there are still uncertainties about its physiological meaning. Glutamate (NMDA) and tachykinin NK1 receptors are required to generate wind-up and therefore a positive modulation between these two receptor types has been suggested by some authors. However, most drugs capable of reducing the excitability of spinal cord neurones, including opioids and NSAIDs, can also reduce or even abolish wind-up. Thus, other theories involving synaptic efficacy, potassium channels, calcium channels, etc, have also been proposed for the generation of this phenomenon. Whatever the mechanisms involved in its generation, wind-up has been interpreted as a system for the amplification in the spinal cord of the nociceptive message that arrives from peripheral nociceptors connected to C-fibres. This probably reflects the physiological system activated in the spinal cord after an intense or persistent barrage of afferent nociceptive impulses. On the other hand, wind-up, central sensitisation and hyperalgesia are not the same phenomena, although they may share common properties. Wind-up can be an important tool to study the processing of nociceptive information in the spinal cord, and the central effects of drugs that modulate the nociceptive system. This paper reviews the physiological and pharmacological data on wind-up of spinal cord neurones, and the perceptual correlates of wind-up in human subjects, in the context of its possible relation to the triggering of hyperalgesic stales, and also the multiple factors which contribute to the generation of wind-up. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：传入通路/生理学镇痛药/药理学麻醉药局部/药理学消炎药非甾类/药理学痛觉过敏/病理生理学炎症离子转运/药物作用模型神经学吗啡/药理学神经纤维/药物作用神经纤维/生理学神经组织蛋白质类/药物作用神经组织蛋白质类/生理学神经痛/病理生理学神经元可塑性/药物作用神经元可塑性/生理学神经元传入/药物作用神经元传入/生理学神经肽类/生理学疼痛感受器/生理学疼痛/药物疗法疼痛/病理生理学受体亲代谢性谷氨酸盐/药物作用受体亲代谢性谷氨酸盐/生理学受体 N-甲基-D-天冬氨酸/药物作用受体 N-甲基-D-天冬氨酸/生理学受体神经激肽1/药物作用受体神经激肽1/生理学反射/生理学脊髓/细胞学脊髓/病理生理学 P物质/生理学突触传递/药物作用内脏/神经支配动物猫人类

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Characterization of antiallodynic actions of ALE-0540, a novel nerve growth factor receptor antagonist, in the rat

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第3期289卷 1271-1276页

作者： Owolabi, JB Rizkalla, G Tehim, A Ross, GM Riopelle, RJ Kamboj, R Ossipov, M Bian, D Wegert, S Porreca, F Lee, DKH Allelix Biopharmaceut Inc Mississauga ON Canada Univ Arizona Hlth Sci Ctr Dept Pharm Tucson AZ USA Queens Univ Dept Med Kingston ON K7L 3N6 Canada

There is growing evidence that nerve growth factor (NGF) may function as a mediator of persistent pain states. We have identified a novel nonpeptidic molecule, ALE-0540, that inhibits the binding of NGF to tyrosine kinase (Trk) A or both p75 and TrkA (IC50 5.88 +/- 1.87 mu M, 3.72 +/- 1.3 mu M, respectively), as well as signal transduction and biological responses mediated by TrkA receptors. ALE-0540 was tested in models of neuropathic pain and thermally-induced inflammatory pain, using two routes of administration, a systemic i.p. and a spinal intrathecal (***.) route. Morphine was also tested for comparison in the antiallodynia model using mechanical stimuli. We show that either i.p. or ***. administration of ALE-0540 in rats produced antiallodynia in the L5/L6 ligation model of neuropathic pain. The calculated A(50) values land 95% confidence intervals) for ALE-0540 administered i.p. and ***, were 38 (17.5-83) mg/kg and 34.6 (17.3-69.4) mu g, respectively. ALE-0540 given ***., at doses of 30 and 60 mu g, also blocked tactile allodynia in the thermal sensitization model. Although morphine displayed greater potency [A(50) value of 7.1 (5.6-8.8) mg/kg] than ALE-0540 in anti-allodynic effect when given i.p. to L5/L6-ligated rats, it was not active when administered ***. These data suggest that a blockade of NGF bioactivity using a NGF receptor antagonist is capable of blocking neuropathic and inflammatory pain and further support the hypothesis that NGF is involved in signaling pathways associated with these pain states. ALE-0540 represents a nonpeptidic small molecule which can be used to examine mechanisms leading to the development of agents for the treatment of pain.

关键词：镇痛药/投药和剂量镇痛药/药理学细胞培养的剂量效应关系药物神经节脊/细胞学神经节脊/生理学杂环化合物 3环/投药和剂量杂环化合物 3环/药理学热温度炎症注射腹腔内注射脊髓吗啡/药理学神经生长因子类/代谢神经痛/病理生理学神经痛/预防和控制神经突/药物作用神经突/生理学神经元传入/药物作用神经元传入/生理学疼痛/病理生理学疼痛/预防和控制磷酰化原癌基因蛋白质类/拮抗剂和抑制剂原癌基因蛋白质类/代谢放射配体测定受体蛋白质酪氨酸激酶类/拮抗剂和抑制剂受体蛋白质酪氨酸激酶类/代谢受体 trkA 受体神经生长因子类/拮抗剂和抑制剂受体神经生长因子类/代谢脊髓/药物作用脊髓/生理学脊神经/药物作用脊神经/生理学动物鸡胚小鼠大鼠

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Spinal nerve injury enhances subthreshold membrane potential oscillations in DRG neurons: relation to neuropathic pain

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JOURNAL OF NEUROPHYSIOLOGY 2000年第1期84卷 205-215页

作者： Liu, CN Michaelis, M Amir, R Devor, M Hebrew Univ Jerusalem Inst Life Sci Dept Cell & Anim Biol IL-91904 Jerusalem Israel Univ Kiel Inst Physiol D-24098 Kiel Germany

Primary sensory neurons with myelinated axons were examined in vitro in excised whole lumbar dorsal root ganglia (DRGs) taken from adult rats up to 9 days after tight ligation and transection of the L-5 spinal nerve (Chung model of neuropathic pain). Properties of subthreshold membrane potential oscillations, and of repetitive spike discharge, were examined. About 5% of the DRG neurons sampled in control DRGs exhibited high-frequency, subthreshold sinusoidal oscillations in their membrane potential at rest (V-r), and an additional 4.4% developed such oscillations on depolarization. Virtually all had noninflected action potentials (A(0) neurons). Amplitude and frequency of subthreshold oscillations were voltage sensitive. A(0) neurons with oscillations at V-r appear to constitute a population distinct from A(0) neurons that oscillate only on depolarization. Axotomy triggered a significant increase in the proportion of neurons exhibiting subthreshold oscillations both at V-r and on depolarization. This change occurred within a narrow time window 16-24 h postoperative. Axotomy also shifted the membrane potential at which oscillation amplitude was maximal to more negative (hyperpolarized) values, and lowered oscillation frequency at any given membrane potential. Most neurons that had oscillations at V-r, or that developed them on depolarization, began to fire repetitively when further depolarized. Spikes were triggered by the depolarizing phase of oscillatory sinusoids. Neurons that did not develop subthreshold oscillations never discharged repetitively and rarely fired more than a single spike or a short burst, on step depolarization. The most prominent spike waveform parameters distinguishing neurons capable of generating subthreshold oscillations, and hence repetitive firing, was their brief postspike afterhyperpolarization (AHP) and their low single-spike threshold. Neurons that oscillated at V-r tended to have a more prolonged spike, with slower rise- and fall-time

关键词：动作电位/生理学轴突切断术电生理学神经节脊/细胞学神经节脊/生理学神经痛/病理生理学神经元传入/生理学周期性大鼠 Wistar 脊神经/损伤脊神经/生理学动物男(雄)性大鼠

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Transmission of chronic nociception by spinal neurons expressing the substance P receptor

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SCIENCE 1999年第5444期286卷 1558-1561页

作者： Nichols, ML Allen, BJ Rogers, SD Ghilardi, JR Honore, P Luger, NM Finke, MP Li, J Lappi, DA Simone, DA Mantyh, PW Univ Minnesota Dept Prevent Sci Minneapolis MN 55455 USA Univ Minnesota Dept Psychiat Minneapolis MN 55455 USA Univ Minnesota Dept Neurosci Minneapolis MN 55455 USA Univ Minnesota Ctr Canc Minneapolis MN 55455 USA Vet Affairs Med Ctr Mol Neurobiol Lab 151 Minneapolis MN 55417 USA Adv Targeting Syst San Diego CA 92121 USA

Substance P receptor (SPR)-expressing spinal neurons were ablated with the selective cytotoxin substance P-saporin. Loss of these neurons resulted in a reduction of thermal hyperalgesia and mechanical allodynia associated with persistent neuropathic and inflammatory pain states. This Loss appeared to be permanent. Responses to mildly painful stimuli and morphine analgesia were unaffected by this treatment. These results identify a target for treating persistent pain and suggest that the small population of SPR-expressing neurons in the dorsal horn of the spinal cord plays a pivotal role in the generation and maintenance of chronic neuropathic and inflammatory pain.

关键词：剂量效应关系药物神经节脊/药物作用神经节脊/生理学免疫毒素类炎症/病理生理学结扎术 N-糖基水解酶类神经痛/药物疗法神经痛/病理生理学疼痛/药物疗法疼痛/病理生理学植物蛋白质类/投药和剂量植物蛋白质类/药理学后角细胞/药物作用后角细胞/生理学受体神经激肽1/代谢核糖体失活蛋白质类 1型脊神经 P物质/投药和剂量 P物质/药理学时间因素动物大鼠

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Coincidental supraorbital neuralgia and sinusitis

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AMERICAN JOURNAL OF RHINOLOGY 1999年第6期13卷 463-468页

作者： Talmi, YP Finkelstein, Y Wolf, M Ben-Shoshan, Y Kronenberg, J Chaim Sheba Med Ctr Dept Otolaryngol Head & Neck Surg IL-52621 Tel Hashomer Israel

Headache interpreted as treatment failure may be encountered after FESS or pharmacological treatment for chronic sinusitis. This persistent symptom may lead, even in the presence of minimal sinus disease, to frequent office visits, medical treatment, primary surgery, and revision procedures. A prospective study of patients with a documented history and imaging-verified sinus disease with persistent atypical refractory headache were evaluated. Diagnostic measures included injection of local anesthetic and response to carbamazepine. Severe neuralgia of the supraorbital nerve was identified in 11 patients with chronic sinusitis, treated either medically or surgically before inclusion in the study. Eight of the patients underwent surgery for sinus disease, and five of them had revision surgery because of persisting complaints. All patients responded favorably to the local injection, and eight were treated with carbamazepine. In certain cases, headache in sinusitis patients may be caused or aggravated by supraorbital neuralgia. Sinus disease is possibly a causative factor but conceivably plays the role of "red herring." This readily diagnosed and treated coexistence may be more prevalent than recognized formerly.

关键词：慢性病队列研究内窥镜检查/方法随访研究神经痛/病因学神经痛/病理生理学神经痛/治疗疼痛测定前瞻性研究疾病严重程度指数鼻窦炎/并发症鼻窦炎/诊断鼻窦炎/外科学鼻窦炎/治疗治疗结果成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人妊娠

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Structural basis of sympathetic-sensory coupling in rat and human dorsal root ganglia following peripheral nerve injury

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JOURNAL OF NEUROCYTOLOGY 1999年第9期28卷 743-761页

作者： Shinder, V Govrin-Lippmann, R Cohen, S Belenky, M Ilin, P Fried, K Wilkinson, HA Devor, M Hebrew Univ Jerusalem Inst Life Sci Dept Cell & Anim Biol IL-91904 Jerusalem Israel Newton Wellesley Hosp Div Neurosurg Wellesley Hills MA 02481 USA Karolinska Inst Dept Neurosci S-17177 Stockholm Sweden

Tyrosine hydroxylase immunocytochemistry was used to reveal the sympathetic postganglionic axons that sprout to form basket-like skeins around the somata of some primary sensory neurons in dorsal root ganglia (DRGs) following sciatic nerve injury. Ultrastructural observations in rats revealed that these sprouts grow on the surface of glial lamellae that form on the neurons. Sciatic nerve injury triggers glial cell proliferation in the DRG, and the formation of multilamellar pericellular onion bulb sheaths, primarily around large diameter DRG neurons. We infer that these glia participate in the sprouting process by releasing neurotrophins and expressing growth supportive cell surface molecules. Many DRG cell somata, and their axons in intact nerves and nerve end neuromas, express alpha 2A adrenoreceptors intracytoplasmically and on their membrane surface. However, sympathetic axons never make direct contacts with the soma membrane. The functional coupling known to occur between sympathetic efferents and DRG neurons must therefore be mediated by the diffusion of neurotransmitter molecules in the extracellular space. Sympathetic basket-skeins were observed in DRGs removed from human neuropathic pain patients, but the possibility of a functional relation between these structures and sensory symptoms remains speculative.

关键词：轴突切断术活组织检查细胞间通讯/生理学神经节脊/病理学神经节脊/超微结构显微镜检查电子神经痛/病理学神经痛/病理生理学神经胶质/细胞学神经元传入/化学神经元传入/酶学神经元传入/超微结构大鼠 Wistar 受体肾上腺素能α2/分析坐骨神经/损伤酪氨酸单氧化酶/分析成年人动物女(雌)性人类男(雄)性中年人大鼠

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Extracellular signal-regulated kinases in the forming and maintaining of neuralgia in rats with chronic constrictive injury

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中国组织工程研究 2005年第14期9卷 225-227页

作者：宋雪松杨桐伟曹君利杜宝东曾因明长春市吉林大学第一医院麻醉科

背景:胞外信号调节激酶(extracellular signal-regulated kinases,ERK)由其特异的上游激酶丝裂原活化蛋白激酶和胞外信号调节激酶激酶(MAPK/ERK kinases,MEK)激活,是细胞生长、记忆和长时程神经元可塑性中的一个重要因素。目的:研究ERK... 详细信息

背景:胞外信号调节激酶(extracellular signal-regulated kinases,ERK)由其特异的上游激酶丝裂原活化蛋白激酶和胞外信号调节激酶激酶(MAPK/ERK kinases,MEK)激活,是细胞生长、记忆和长时程神经元可塑性中的一个重要因素。目的:研究ERK在慢性压迫性损伤引起的神经痛形成和维持中的作用。设计:以实验动物为研究对象,随机对照的验证性研究。单位:一所大学医院的麻醉科。材料:实验于2003-09/2004-06在江苏省麻醉医学研究所完成,选择雄性清洁级SD大鼠115只,体质量220-300g,由徐州医学院实验动物中心提供,分笼饲养,室温维持20-25℃,自然照明,自由饮水和摄食。干预:慢性压迫性损伤(chronic constriction injury,CCI)模型建立后第5天,采用Mestre直接鞘内注射方法行不同浓度的U0126注射,同时在对照组给予鞘内注射无菌的50g/L二甲基亚砜。主要观察指标:采用von Frey纤维丝和热痛刺激仪观察CCI大鼠鞘内应用U0126后机械性痛敏和热痛敏阈值的变化,同时应用免疫组织化学和免疫印记方法观察对大鼠脊髓背角内ERK活性的影响。结果:CCI引起大鼠脊髓背角内ERK活性的增强,鞘内注射U0126抑制ERK活性的同时能明显减轻由CCI导致的大鼠机械性痛敏和热痛敏。结论:脊髓背角内细胞外信号调节激酶的激活和转位与CCI引起的神经痛的形成和维持有关。

关键词：大鼠 Sprague-Dawley 脊髓/酶学神经痛/病理生理学痛觉过敏/病理生理学细胞外信号调节MAP激酶类/生理学细胞外信号调节MAP激酶类/代谢大鼠动物男(雄)性

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鞘内注射BN52021对神经病理痛大鼠痛阈及脊髓c-fos表达的影响

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陕西医学杂志 2009年第5期38卷 532-534,569页

作者：马国平杨京利田玉科刘菊英湖北省十堰市郧阳医学院附属太和医院麻醉科华中科技大学同济医院麻醉科武汉430070

目的:研究血小板活化因子受体拮抗剂BN52021鞘内给药对保留性神经损伤(SNI)神经病理痛大鼠痛阈及脊髓c-fos表达的影响。方法:将40只Sprague-Dawley大鼠鞘内置PE-10导管后随机分为4组:Sham组,SNI组,SNI+DMSO组和SNI+BN52021组,建立SNI疼... 详细信息

目的:研究血小板活化因子受体拮抗剂BN52021鞘内给药对保留性神经损伤(SNI)神经病理痛大鼠痛阈及脊髓c-fos表达的影响。方法:将40只Sprague-Dawley大鼠鞘内置PE-10导管后随机分为4组:Sham组,SNI组,SNI+DMSO组和SNI+BN52021组,建立SNI疼痛模型,手术后第1、3、5、7、10和14天鞘内给药并测痛阈,第14天取大鼠L4～6段脊髓,免疫组化染色检测Fos免疫阳性细胞。结果:SNI神经损伤大鼠机械缩爪阈降低(P<0.05),同侧脊髓背角浅层内Fos阳性神经元明显增多(P<0.05);BN52021鞘内注射减少脊髓背角神经元c-fos的表达,同时伴有大鼠触觉异常痛敏的减轻。各组大鼠辐射热缩爪潜伏期无明显差异。结论:鞘内注射BN52021可减轻SNI大鼠触觉异常痛敏,抑制神经损伤后脊髓背角c-fos表达增强。

关键词：神经痛/病理生理学神经痛/药物疗法二裂银杏/治疗应用基因,fos/代谢模型,动物大鼠

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Measurement of nerve dysfunction in neuropathic pain.

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Current review of pain 2000年第5期4卷 388-394页

作者： Konen, A. Progressive Pain Management Center 2811 Lemmon Avenue East Dallas 75204 TX United States

Neuropathic pain is difficult to diagnose and treat. Both can be made easier if the nerve dysfunction can be quantified. The two basic modes of evaluation are subjective and objective. This article presents currently used methods in both arenas. Discussion is also given to some basic neurophysiology necessary to understanding the use of these testing methods.

关键词：神经传导神经痛/诊断神经痛/病理生理学神经痛/治疗体格检查人类

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