Reduced nerve injury-induced neuropathic pain in kinin B1 receptor knock-out mice
Reduced nerve injury-induced neuropathic pain in kinin B1 receptor knock-out mice
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DOI：
10.1523/jneurosci.2466-04.2005
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发表时间：
2005-03-02
影响因子：
5.3
通讯作者：
Calixto, JB
中科院分区：
文献类型：
--
作者：
Ferreira, J;Beirith, A;Calixto, JB
外周神经损伤通常导致以自发性疼痛、异常性疼痛和痛觉过敏为特征的持续性神经性疼痛病症。神经损伤伴有局部炎症反应，其中神经相关细胞和免疫细胞释放几种原伤害感受介质。激肽B-1受体很少在非创伤组织中表达，但它们可以在组织损伤后表达。由于B-1受体介导慢性炎性疼痛过程，我们使用受体基因缺失的小鼠研究了它们在神经病理性疼痛中的参与。在没有神经病变的情况下，我们发现B-1受体敲除小鼠和129/J野生型小鼠对热或机械刺激的缩爪反应没有差异。部分结扎野生型小鼠的坐骨神经在神经损伤同侧的爪中产生热阈值和机械阈值的深刻且持久的降低。在假手术动物和病变对侧爪中阈值均未改变。消融B-1受体的基因导致机械异常性疼痛和热痛觉过敏的早期阶段显著减少。此外，用B-1选择性受体拮抗剂des-Arg（9）-[Leu（8）]-缓激肽全身治疗可减少野生型小鼠神经损伤后7- 28天观察到的已建立的机械性异常性疼痛。部分坐骨神经结扎诱导野生型小鼠同侧爪、坐骨神经和脊髓中B-1受体mRNA的上调。总之，激肽B-1受体活化似乎是神经性疼痛发展所必需的，这表明口服选择性B-1受体拮抗剂在慢性疼痛的管理中可能具有治疗潜力。
Injury to peripheral nerves often results in a persistent neuropathic pain condition that is characterized by spontaneous pain, allodynia, and hyperalgesia. Nerve injury is accompanied by a local inflammatory reaction in which nerve-associated and immune cells release several pronociceptive mediators. Kinin B-1 receptors are rarely expressed in nontraumatized tissues, but they can be expressed after tissue injury. Because B-1 receptors mediate chronic inflammatory painful processes, we studied their participation in neuropathic pain using receptor gene-deleted mice. In the absence of neuropathy, we found no difference in the paw-withdrawal responses to thermal or mechanical stimulation between B-1 receptor knock-out mice and 129/J wild-type mice. Partial ligation of the sciatic nerve in the wild-type mouse produced a profound and long-lasting decrease in thermal and mechanical thresholds in the paw ipsilateral to nerve lesion. Threshold changed neither in the sham-operated animals nor in the paw contralateral to lesion. Ablation of the gene for the B-1 receptor resulted in a significant reduction in early stages of mechanical allodynia and thermal hyperalgesia. Furthermore, systemic treatment with the B-1 selective receptor antagonist des-Arg(9)-[Leu(8)]-bradykinin reduced the established mechanical allodynia observed 7-28d after nerve lesion in wild-type mice. Partial sciatic nerve ligation induced an upregulation in B-1 receptor mRNA in ipsilateral paw, sciatic nerve, and spinal cord of wild-type mice. Together, kinin B-1 receptor activation seems to be essential to neuropathic pain development, suggesting that an oral-selective B-1 receptor antagonist might have therapeutic potential in the management of chronic pain.