Banik R K, Kozaki Y, Sato J, Gera L, Mizumura K
Department of Neural Regulation, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
J Neurophysiol. 2001 Dec;86(6):2727-35. doi: 10.1152/jn.2001.86.6.2727.
Bradykinin (BK), which has potent algesic and sensitizing effect on nociceptors, is of current interest in understanding the mechanisms of chronic pain. BK response is mediated by B2 receptor in normal conditions; however, findings that B1 receptor blockade alleviated hyperalgesia in inflammation have been highlighting the role of B1 receptor in pathological conditions. It has not yet been clear whether nociceptor activities are modified by B1 receptor agonists or antagonists during inflammation. In addition, previous studies reported the change in BK sensitivity of nociceptors during short-lasting inflammation, and data in persistent inflammation are lacking. Therefore we investigated whether an experimentally induced persistent inflammatory state modulates the BK sensitivity of nociceptors and which receptor subtype plays a more important role in this condition. Complete Freund's adjuvant was injected into the rat-tail and after 2-3 wk, persistent inflammation developed, which was prominent in the ankle joint. Using an in vitro skin-saphenous nerve preparation, single-fiber recordings were made from mechano-heat sensitive C-fiber nociceptors innervating rat hairy hindpaw skin, and their responses were compared with those obtained from C-fibers tested similarly in normal animals. BK at 10(-8) M excited none of the 10 C-fibers in normal animals while it excited 5 of 11 (45%) C-fibers of inflamed animals, and at 10(-6) M BK excited all of the 11 inflamed C-fibers (or 94% of 36 tested C-fibers) but only 4 of 10 (or 45% of 58 tested C-fibers) in normal animals. Thus the concentration-response curves based on the incidence of BK induced excitation, and the total number of impulses evoked in response to BK were significantly shifted to the left. Moreover, an increased percentage of the inflamed C-fibers responded to 10(-6) M BK with bursting or high-frequency discharges. Thirty-percent of inflamed C-fibers had spontaneous activity, and these fibers showed comparatively less tachyphylaxis to consecutive second and third 10(-6) M BK stimulation. A B2 receptor antagonist (D-Arg-[Hyp3, Thi5,8,D-phe7]-BK) completely eliminated BK responses in inflamed rats, while B1 receptor antagonists (B 9958 and Des-Arg9-[Leu8]-BK) had no effect. Selective B1 receptor agonist (Des-Arg10-Kallidin) excited 46% (n = 13) of inflamed C-fibers at 10(-5) M concentration, which is 1,000 times higher than that of BK needed to excite the same percentage of inflamed C-fibers. We conclude that in chronically inflamed tissue, sensitivity of C-fiber nociceptors to BK, which is B2 receptor mediated, is strongly increased and that B1 receptor may not be important to a persistent inflammatory state, at least at the primary afferent level.
缓激肽（BK）对伤害感受器具有强大的致痛和致敏作用，目前在理解慢性疼痛机制方面备受关注。在正常情况下，BK反应由B2受体介导；然而，B1受体阻断可减轻炎症性痛觉过敏的研究结果，凸显了B1受体在病理状态下的作用。炎症期间，B1受体激动剂或拮抗剂是否会改变伤害感受器的活动尚不清楚。此外，先前的研究报道了短暂炎症期间伤害感受器对BK敏感性的变化，但缺乏持续性炎症的数据。因此，我们研究了实验诱导的持续性炎症状态是否会调节伤害感受器对BK的敏感性，以及哪种受体亚型在这种情况下发挥更重要的作用。将完全弗氏佐剂注射到大鼠尾部，2 - 3周后出现持续性炎症，踝关节处尤为明显。使用体外皮肤 - 隐神经标本，从支配大鼠后爪多毛皮肤的机械热敏感C纤维伤害感受器进行单纤维记录，并将其反应与正常动物中类似测试的C纤维反应进行比较。10^(-8) M的BK未激发正常动物的10根C纤维中的任何一根，而激发了11根炎症动物C纤维中的5根（45%）；10^(-6) M的BK激发了所有11根炎症C纤维（或36根测试C纤维中的94%），但仅激发了正常动物10根中的4根（或58根测试C纤维中的45%）。因此，基于BK诱导兴奋发生率和对BK诱发的总冲动数的浓度 - 反应曲线显著左移。此外，炎症C纤维中对10^(-6) M BK以爆发或高频放电反应的百分比增加。30%的炎症C纤维有自发活动，这些纤维对连续的第二次和第三次10^(-6) M BK刺激表现出相对较少速发耐受。B2受体拮抗剂（D - Arg - [Hyp3, Thi5,8,D - phe7] - BK）完全消除了炎症大鼠的BK反应，而B1受体拮抗剂（B 9958和Des - Arg9 - [Leu8] - BK）无效。选择性B1受体激动剂（Des - Arg10 - Kallidin）在10^(-5) M浓度下激发了46%（n = 13）的炎症C纤维，这一浓度比激发相同百分比炎症C纤维所需的BK浓度高1000倍。我们得出结论，在慢性炎症组织中，C纤维伤害感受器对BK（由B2受体介导）的敏感性显著增加，并且B1受体对持续性炎症状态可能不重要，至少在初级传入水平上是这样。
