Khasar S G, Miao F J, Levine J D
Department of Anatomy, University of California, San Francisco 94143, USA.
Neuroscience. 1995 Nov;69(2):685-90. doi: 10.1016/0306-4522(95)00280-v.
While B2 receptors mediate pain and hyperalgesia induced by bradykinin, in normal rats, recent reports indicate that, in the setting of inflammation, B1 receptors also mediate pain and hyperalgesia. Since bradykinin-induced hyperalgesia in normal rats is mediated by prostaglandins released from the postganglionic sympathetic neurons, we have evaluated the contribution of the sympathetic nervous system to the hyperalgesia induced by bradykinin, a preferential B2-receptor agonist, and des-Arg9-bradykinin, a major metabolite of bradykinin and a selective B1-receptor agonist. Mechanical hyperalgesia was quantified by the Randall-Selitto paw-withdrawal method. Inflammation was induced by injecting Complete Freund's Adjuvant into the left hindpaw of the rat and testing mechanical nociceptive threshold in the right hindpaw after injecting B1 or B2 agonists and/or antagonists. Sympathectomy was achieved by surgically removing sympathetic ganglia L1-L4. Rats were used 48 h post-adjuvant injection. In the normal rat, intradermal injection of bradykinin but not des-Arg9-bradykinin, into the dorsal surface of the hindpaw, produced a dose-dependent decrease in mechanical nociceptive threshold. NPC 17731, a B2-receptor antagonist, but not des-Arg9-[Leu8]-bradykinin, a B1-receptor antagonist, almost completely inhibited the decrease in mechanical threshold, suggesting that bradykinin hyperalgesia in the normal rat hindpaw was mediated by B2 receptors. In rats whose left paws were treated, 48 h earlier, with adjuvant, intradermal injection of bradykinin or des-Arg9-bradykinin, into the right paw produced dose-dependent hyperalgesia. Bradykinin hyperalgesia was partially inhibited by NPC 17731, and the residual part by des-Arg9,[Leu8]-bradykinin. des-Arg9-bradykinin hyperalgesia was inhibited by des-Arg9,[Leu8]-bradykinin but not by NPC17731. These results suggest that in the setting of inflammation, bradykinin hyperalgesia was mediated by both B1 and B2 receptors, and that des-Arg9-bradykinin hyperalgesia was mediated by the B1 receptor. Forty-eight hours after injection of complete Freund's adjuvant, in sympathectomized rats, bradykinin or des-Arg9-bradykinin failed to produce hyperalgesia, suggesting that intact sympathetic postganglionic neurons are required for the hyperalgesia produced by these agents in this model. These results are consistent with the suggestions that B2 receptors mediate bradykinin-induced cutaneous hyperalgesia in the normal rat hindpaw. The hyperalgesia induced by bradykinin, 48 h post injection of complete Freund's adjuvant is mediated by both B1 and B2 receptors, that by des-Arg9-bradykinin is mediated by B1 receptors. The hyperalgesia induced by both agents is dependent on the presence of intact sympathetic postganglionic neurons.
虽然B2受体介导缓激肽诱导的疼痛和痛觉过敏，但在正常大鼠中，最近的报告表明，在炎症状态下，B1受体也介导疼痛和痛觉过敏。由于正常大鼠中缓激肽诱导的痛觉过敏是由节后交感神经元释放的前列腺素介导的，我们评估了交感神经系统对缓激肽（一种选择性B2受体激动剂）和去-Arg9-缓激肽（缓激肽的主要代谢产物和选择性B1受体激动剂）诱导的痛觉过敏的作用。通过Randall-Selitto paw-withdrawal方法对机械性痛觉过敏进行定量。通过手术切除交感神经节L1-L4实现交感神经切除术。在佐剂注射后48小时使用大鼠。在正常大鼠中，将缓激肽而非去-Arg9-缓激肽皮内注射到后爪背表面，会导致机械性痛觉阈值呈剂量依赖性降低。B2受体拮抗剂NPC 17731而非B1受体拮抗剂去-Arg9-[Leu8]-缓激肽几乎完全抑制了机械阈值的降低，这表明正常大鼠后爪中缓激肽诱导的痛觉过敏是由B2受体介导的。在48小时前左爪用佐剂处理的大鼠中，将缓激肽或去-Arg9-缓激肽皮内注射到右爪会产生剂量依赖性痛觉过敏。缓激肽诱导的痛觉过敏被NPC 17731部分抑制，剩余部分被去-Arg9,[Leu8]-缓激肽抑制。去-Arg9-缓激肽诱导的痛觉过敏被去-Arg9,[Leu8]-缓激肽抑制，但不被NPC17731抑制。这些结果表明，在炎症状态下，缓激肽诱导的痛觉过敏由B1和B2受体共同介导，而去-Arg9-缓激肽诱导的痛觉过敏由B1受体介导。在注射完全弗氏佐剂48小时后，在交感神经切除的大鼠中，缓激肽或去-Arg9-缓激肽未能产生痛觉过敏，这表明在该模型中，这些药物诱导的痛觉过敏需要完整的节后交感神经元。这些结果与以下观点一致：B2受体介导正常大鼠后爪中缓激肽诱导的皮肤痛觉过敏。注射完全弗氏佐剂48小时后，缓激肽诱导的痛觉过敏由B1和B2受体共同介导，去-Arg9-缓激肽诱导的痛觉过敏由B1受体介导。两种药物诱导的痛觉过敏均依赖于完整的节后交感神经元的存在。
