CN113181174A - Bl-1249在制备治疗神经病理性疼痛的药物中的应用 - Google Patents
Bl-1249在制备治疗神经病理性疼痛的药物中的应用 Download PDFInfo
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Abstract
本发明公开了BL‑1249在制备治疗神经病理性疼痛的药物中的应用。动物疼痛行为学验证，背根神经节注射双孔钾通道TREK1和TREK2的开放剂BL‑1249 10μM后，坐骨神经部分损伤模型（SNI）大鼠以及前驱糖尿病神经病理性痛（PDNP）大鼠模型的机械刺激疼痛明显减轻。可见，TREK1和TREK2通道开放剂BL1249可以有效地缓解SNI及PDNP模型的机械刺激痛觉敏化。同时在离体膜片钳实验中发现：BL‑1249均可降低两种模型损伤后背根神经节神经元的高频放电和兴奋性。综上所述，在背根神经节给予双孔钾通道TREK1和TREK2的开放剂BL‑1249对神经病理性疼痛的缓解作用，为神经病理性疼痛的治疗提供了新的靶点药物。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种钾离子通道开放剂BL-1249在制备治疗神经病理性疼痛的药物中的应用。
背景技术
众所周知，疼痛是一种复杂的体验与经历，包括感觉识辨、情绪动机和认知评价三个主要组成部分。目前认为，当疼痛加剧或机体受到炎症或各种损伤侵袭时，疼痛不再起到保护作用，逐渐发展为慢性痛，不仅可以造成感觉功能障碍（自发性疼痛，痛觉过敏和异常痛敏），还会通过上行传导通路影响到诸多高级脑功能。神经病理性痛是临床治疗慢性痛的重点和难点问题之一。神经病理性痛（neuropathic pain）是由外周或中枢水平躯体感觉系统的损伤和疾病而直接造成的疼痛。其发病机制复杂，迁延不愈，可累及多部位神经系统，包括周围神经损伤（糖尿病神经病理性疼痛、外周神经损伤、带状疱疹后神经痛）和中枢神经损伤（中风后疼痛、脊髓损伤、多发性硬化等）。
在过去的几十年里，虽然疼痛神经生物学的机制研究取得了很大的进展，但是在治疗慢性疼痛的镇痛药物的研发上依然面临很大挑战(Woolf, 2010)。可以影响疼痛调节系统的药物成分依然是疼痛治疗的主要选择。在临床中，传统的镇痛药物如阿片类仍然是中重度疼痛治疗的重要方案，虽然阿片类镇痛药可以缓解急性痛患者手术或术后疼痛，但对慢性神经病理性痛的治疗效果甚微，同时，阿片类物质可以使疼痛的敏感性发生改变（如痛敏）。NSAIDs (非甾体类抗炎药物)可以通过抑制PGE2的合成对炎性痛起到镇痛作用，进而减少外周和中枢敏化，但对长期慢性神经病理性疼痛的疗效不佳，并有明显的胃肠道和心血管系统的副作用。三环类抗抑郁药和抗惊厥药被应用于各种神经病理性痛的治疗。例如α2结合物普瑞巴林和加巴喷定可以作用于VGCCs而作为治疗神经病理性痛的有效药物。但同样因作用靶分子分布广泛而具有明显的副作用。近年一些作用于新近发现的分子靶点的药物也在进行临床试验，鞘内注射齐考诺肽可以结合孔形α亚单位阻断N型VGCC来减轻剧烈疼痛和慢性痛。TRPV1拮抗剂在临床II期试验中可以有效的减轻骨关节疼痛。
双孔钾通道TREK1和TREK2（统称TREK1/2）是一种机械门控的，可被花生四烯酸激活的钾通道；两者的基因序列约63%具有一致性，因此这两种通道也具有许多相似的功能特性，例如TREK1/2两种通道均在DRG神经元的中、小细胞上表达，均受脂质、酸性环境以及细胞肿胀等因素调控，可被不饱和脂肪酸激活对细胞产生保护作用；被PKA和PKC的磷酸化作用所抑制；它们对偏酸的PH敏感，细胞内、外的酸会抑制TREK1/2通道的开放（Honore,2007; Lesage et al., 2000）。另外发现TREK1/2通道在疼痛感知、抑郁以及炎症中也发挥着重要作用。例如TREK1－/－的动物出现机械刺激和热刺激的痛觉敏化（Alloui et al.,2006），而TREK2的功能目前研究较少，但有实验证实激活DRG神经元上的TREK2通道可以减轻神经病理性疼痛（Lesage et al., 2000）；同样TREK2也参与维持静息膜电位水平，激活该通道可以降低神经细胞的兴奋性并减少神经递质的释放。
发明内容
为解决上述问题，本发明提供了一种BL-1249在制备治疗神经病理性疼痛的药物中的应用。
为实现上述目的，本发明采取的技术方案为：
BL-1249在制备治疗神经病理性疼痛的药物中的应用。
动物疼痛行为学验证，背根神经节注射双孔钾通道TREK1和TREK2的开放剂BL-1249 10 μM后，坐骨神经部分损伤模型（SNI）大鼠的机械刺激疼痛和热刺激疼痛均明显减轻。可见，TREK1和TREK2通道开放剂BL1249可以有效地缓解坐骨神经分支损伤模型（Sparednerve injury, SNI）的机械刺激痛觉敏化。
TREK1和TREK2通道开放剂BL1249可以有效地缓解前驱糖尿病模型动物的神经病理性疼痛。
在离体膜片钳实验中发现：BL-1249可以降低损伤后背根神经节神经元的高频放电和兴奋性。
本发明以外周神经系统的TREK1和TREK2为靶点，发现：在背根神经节给予双孔钾通道TREK1和TREK2的开放剂BL-1249对神经病理性疼痛的缓解作用，为神经病理性疼痛的治疗提供了新的靶点药物。
附图说明
图1为BL1249对坐骨神经分支损伤模型（SNI）模型动物痛觉敏化的影响。
图2为BL1249对SNI模型动物DRG神经元兴奋的影响。
图3为BL1249对前驱糖尿病神经病理性痛（PDNP）模型动物痛觉敏化行为的影响。
图4为PDNP模型动物DRG神经元兴奋的影响。
图5为药物的作用位点和作用机制示意图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。
如图1所示，TREK1和TREK2通道开放剂BL1249可以有效地缓解坐骨神经分支损伤模型（Spared nerve injury, SNI）的机械刺激痛觉敏化。（A）SNI模型7天后，模型动物出现明显的机械刺激痛觉敏化，可表现为机械刺激足缩反应阈值（paw withdrawal mechanicalthreshold, PWMT）明显下降（P < 0.01）。（B）椎间孔背根神经节（dorsal root ganglia,DRG）内注射BL1249不影响正常动物的机械刺激足缩反应阈值（P > 0.05）。(C) DRG 内注射BL1249明显缓解SNI模型动物的机械刺激痛觉敏化。注射后4 h到8 h，PWMT明显升高（P <0.05），注射后6 h，PWMT接近基础阈值水平。
如图2所示，BL1249可以有效地降低SNI动物DRG神经元的超兴奋性。（A）给予BL1249 （10 μM）前、后SNI 2W 组DRG神经元放电的典型图。（B）BL1249不改变SNI组神经元动作电位的幅度（P > 0.05）。（C）给予BL1249后，SNI组神经元动作电位的放电基强度明显升高（P < 0.05）。（D）给予BL1249后，SNI组神经元动作电位的阈值明显升高（P < 0.05）。（E. F）BL1249不改变SNI组神经元的膜电位以及后超极化电位（P > 0.05）。（G）给予BL1249后，SNI组神经元动作电位的半宽明显变大（P < 0.05）。（H）在500 pA 电流刺激下，给予BL1249后，SNI组神经元的放电频率明显下降（P < 0.05）
如图3所示，TREK1和TREK2通道开放剂BL1249可以有效地缓解前驱糖尿病模型动物的神经病理性疼痛（prediabetic neuropathic pain, PDNP）。（A） 高脂、高糖喂养60天的前驱糖尿病模型动物会出现明显的机械刺激痛觉敏化（P < 0.01）。（B）DRG 内注射BL1249明显缓解前驱糖尿病模型动物的机械刺激痛觉敏化（P < 0.01）。
如图4所示，BL1249可以有效地降低PDNP动物DRG神经元的超兴奋性。（A）浴槽内给予BL1249（10 μM）前、后PDNP组DRG神经元放电变化。（B）BL1249不改变PDNP组神经元动作电位的幅度（P > 0.05）。（C）给予BL1249后，PDNP组神经元动作电位的放电基强度明显升高（P< 0.05）。（D）给予BL1249后，PDNP组神经元动作电位的阈值明显升高（P < 0.05）。（E. F）BL1249不改变PDNP组神经元的膜电位以及后超极化电位（P > 0.05）。（G）给予BL1249后，PDNP组神经元动作电位的半宽明显变大（P < 0.05）。（H）给予BL1249后，PDNP组神经元的放电频率明显下降（P < 0.05）。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变化或修改，这并不影响本发明的实质内容。在不冲突的情况下，本申请的实施例和实施例中的特征可以任意相互组合。
Claims (4)
1.BL-1249在制备治疗神经病理性疼痛的药物中的应用。
2.如权利要求1所述的应用，其特征在于：TREK1和TREK2通道开放剂BL1249可以有效地缓解坐骨神经分支损伤模型的机械刺激痛觉敏化。
3.如权利要求1所述的应用，其特征在于：TREK1和TREK2通道开放剂BL1249可以有效地缓解前驱糖尿病模型动物的神经病理性疼痛。
4.如权利要求1所述的应用，其特征在于：BL-1249可以降低两种模型动物损伤后背根神经节神经元的高频放电和兴奋性。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114146162A (zh) * | 2021-12-21 | 2022-03-08 | 青岛恩普生物技术有限公司 | 一种重组人血小板衍生生长因子pdgf在治疗慢性神经病理性疼痛中的应用 |
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Non-Patent Citations (2)
| Title |
|---|
| GUADALUPE GARCÍA等: "PKC-and PKA-dependent phosphorylation modulates TREK-1 function in nave and neuropathic rats", 《JOURNAL OF NEUROCHEMISTRY》 * |
| 赵欣等: "糖尿病与神经病理性疼痛和瘙痒", 《基础医学与临床》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114146162A (zh) * | 2021-12-21 | 2022-03-08 | 青岛恩普生物技术有限公司 | 一种重组人血小板衍生生长因子pdgf在治疗慢性神经病理性疼痛中的应用 |
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