Spinal dynorphin and bradykinin receptors maintain inflammatory hyperalgesia.
Spinal dynorphin and bradykinin receptors maintain inflammatory hyperalgesia.
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DOI：
10.1016/j.jpain.2008.06.005
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Lai J
中科院分区：
文献类型：
--
作者：
Luo MC;Chen Q;Ossipov MH;Rankin DR;Porreca F;Lai J
在多种慢性疼痛的实验模型中观察到脊髓中内源性阿片样物质强啡肽A的上调。最近的研究结果表明，强啡肽A在缓激肽受体的直接兴奋作用，促进神经损伤大鼠的痛觉过敏，其上调可能会促进，而不是抵消，增强伤害性输入由于损伤。在这里，我们研究了一个模型的炎症疼痛单侧注射完全弗氏佐剂（CFA）到大鼠后爪。CFA注射后6小时，大鼠表现出触觉超敏反应和热痛觉过敏在发炎的爪子，而前强啡肽的成绩单在腰髓中的显着升高，在第3天，但不是在6小时。热痛觉过敏在第3天，但不是在6小时，CFA注射后被阻断鞘内注射抗强啡肽抗血清或缓激肽受体拮抗剂。后者的抗痛觉过敏作用不是由于缓激肽的从头生产或脊髓缓激肽受体的上调。这些数据表明，脊髓强啡肽升高外周炎症介导慢性炎症性痛觉过敏。缓激肽受体拮抗剂的抗痛觉过敏作用需要存在上调的脊髓强啡肽，但不是从头生产的缓激肽，支持我们的假设，病理水平的强啡肽可能激活脊髓缓激肽受体介导炎性痛觉过敏。这项研究表明，慢性外周炎症诱导内源性阿片肽强啡肽的显着上调。脊髓强啡肽水平的升高和脊髓缓激肽受体的激活对于维持炎性痛觉过敏是必不可少的。结果表明，阻滞脊髓缓激肽受体可能对慢性炎性疼痛具有治疗潜力。
An upregulation of the endogenous opioid, dynorphin A, in the spinal cord is seen in multiple experimental models of chronic pain. Recent findings implicate a direct excitatory action of dynorphin A at bradykinin receptors to promote hyperalgesia in nerve injured rats, and its upregulation may promote, rather than counteract, enhanced nociceptive input due to injury. Here we examined a model of inflammatory pain by unilateral injection of Complete Freund’s Adjuvant (CFA) into the rat hind paw. Rats exhibited tactile hypersensitivity and thermal hyperalgesia in the inflamed paw by 6 hr after CFA injection, while a significant elevation of prodynorphin transcripts in the lumbar spinal cord was seen at day 3 but not at 6 hr. Thermal hyperalgesia at day 3, but not at 6 hr, after CFA injection was blocked by intrathecal administration of anti-dynorphin antiserum or by bradykinin receptor antagonists. The antihyperalgesic effect of the latter was not due to de novo production of bradykinin or upregulation of spinal bradykinin receptors. These data suggest that elevated spinal dynorphin upon peripheral inflammation mediates chronic inflammatory hyperalgesia. The antihyperalgesic effect of bradykinin receptor antagonists requires the presence of upregulated spinal dynorphin but not of de novo production of bradykinin, supporting our hypothesis that pathological levels of dynorphin may activate spinal bradykinin receptors to mediate inflammatory hyperalgesia. This study shows that chronic peripheral inflammation induces a significant upregulation of the endogenous opioid peptide dynorphin. Elevated levels of spinal dynorphin and activation of spinal bradykinin receptors are essential to maintain inflammatory hyperalgesia. The results suggest that blockade of spinal bradykinin receptors may have therapeutic potential in chronic inflammatory pain.
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