Khan A A, Raja S N, Manning D C, Campbell J N, Meyer R A
Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland 21205.
Somatosens Mot Res. 1992;9(2):97-106. doi: 10.3109/08990229209144765.
The endogenous peptide bradykinin is found in plasma and inflammatory exudates and has been implicated as a chemical mediator of inflammatory pain and hyperalgesia. Two subtypes of bradykinin receptors, B1 and B2, have been described, and antagonists for the receptor subtypes have been synthesized. The bradykinin analogs [desArg9,Leu8]BK and DArg[Hyp3,DPhe7]BK have been reported to have antagonist activity at the B1 and B2 bradykinin receptors in smooth muscle, respectively. Behavioral studies in rats indicate that the bradykinin analogs can block the algesic effects of bradykinin. We wished to determine the effects of bradykinin and the bradykinin analogs (B1 and B2 analogs, respectively) on cutaneous nociceptors in the monkey. In addition, we wished to determine the type of bradykinin receptor that mediates the sensitizing effects of bradykinin. Recordings were made from single C-fiber and A-fiber nociceptive afferents (CMHs and AMHs) that innervated hairy skin. Heat sensitivity before and after the injections was determined with a heat test sequence consisting of stimuli that ranged, in 1 degree C increments, from 41 degrees to 49 degrees C. Intradermal injections of vehicle (neutral normal saline) failed to alter the heat response of CMHs. Bradykinin (10 nmol in 10 microliters) evoked activity in 6 of 10 CMHs and sensitized all the fibers to heat stimuli. After the bradykinin injection, the mean heat threshold of the CMHs decreased from 44 +/- 0.5 degrees to 42.7 +/- 0.5 degrees C (mean +/- SEM, p less than 0.02), and the total response to the heat test sequence increased by 87% (p less than 0.002). In a related psychophysical study in human volunteers, the same dose of bradykinin resulted in a comparable (115%) increase in ratings of pain (Manning et al., 1991). Bradykinin also evoked activity in 10 of 17 AMHs and sensitized 8 AMHs to heat stimuli. Bradykinin failed to alter the threshold for activation of CMHs to mechanical stimuli as measured by application of von Frey hairs to the receptive field. In contrast to bradykinin, intradermal injection of the B1 and B2 analogs (10 nmol in 10 microliters) evoked activity in 2 of 6 and 0 of 5 CMHs, respectively. A noteworthy finding was that both analogs enhanced the response of CMHs to heat stimuli by 50% (B1 analog, 1.5 +/- 0.1; B2 analog, 1.5 +/- 0.2). The B1 (n = 10) and B2 (n = 5) analogs did not evoke activity in any of the 15 AMHs tested.(ABSTRACT TRUNCATED AT 400 WORDS)
内源性肽缓激肽存在于血浆和炎性渗出物中，被认为是炎性疼痛和痛觉过敏的化学介质。已描述了缓激肽受体的两种亚型，即B1和B2，并且已合成了针对这些受体亚型的拮抗剂。据报道，缓激肽类似物[去精氨酸9，亮氨酸8]缓激肽和D - 精氨酸[Hyp3，DPhe7]缓激肽分别在平滑肌的B1和B2缓激肽受体上具有拮抗活性。对大鼠的行为学研究表明，这些缓激肽类似物可以阻断缓激肽的致痛作用。我们希望确定缓激肽和缓激肽类似物（分别为B1和B2类似物）对猴皮肤伤害感受器的影响。此外，我们希望确定介导缓激肽致敏作用的缓激肽受体类型。从支配有毛皮肤的单根C纤维和A纤维伤害性传入神经（CMH和AMH）进行记录。注射前后的热敏感性通过由41℃至49℃、以1℃递增的刺激组成的热测试序列来确定。皮内注射赋形剂（中性生理盐水）未能改变CMH的热反应。缓激肽（10纳摩尔溶于10微升）在10根CMH中的6根中诱发活性，并使所有纤维对热刺激敏感。注射缓激肽后，CMH的平均热阈值从44±0.5℃降至42.7±0.5℃（平均值±标准误，p＜0.02），并且对热测试序列的总反应增加了87%（p＜0.002）。在一项针对人类志愿者的相关心理物理学研究中，相同剂量的缓激肽导致疼痛评分可比地增加了115%（Manning等人，1991年）。缓激肽还在17根AMH中的10根中诱发活性，并使8根AMH对热刺激敏感。缓激肽未能改变通过将von Frey毛应用于感受野所测量的CMH对机械刺激的激活阈值。与缓激肽相反，皮内注射B1和B2类似物（10纳摩尔溶于10微升）分别在6根CMH中的2根和5根CMH中的0根中诱发活性。一个值得注意的发现是，两种类似物均使CMH对热刺激的反应增强了50%（B1类似物，1.5±0.1；B2类似物，1.5±0.2）。B1（n = 10）和B2（n = 5）类似物在测试的15根AMH中均未诱发活性。（摘要截断于400字）
