Antinociceptive profile of the pseudopeptide B-2 bradykinin receptor antagonist NPC 18688 in mice
Antinociceptive profile of the pseudopeptide B-2 bradykinin receptor antagonist NPC 18688 in mice
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DOI：
10.1111/j.1476-5381.1996.tb15226.x
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发表时间：
1996-02-01
影响因子：
7.3
通讯作者：
Calixto, JB
中科院分区：
文献类型：
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作者：
Correa, CR;Kyle, DJ;Calixto, JB
1研究新开发的伪肽B-2受体拮抗剂鼻咽癌18688对小鼠不同伤害性感受模型的局部和全身抗痛觉作用。2预先给药30min，鼻咽癌18688(10-300nmol·kg~(-1)，ip)。对醋酸(0.6%)、乙酰胆碱(ACh，4.5 mg·kg~(-1))或高岭土(50 mg·kg~(-1))所致的腹壁收缩有剂量依赖性抑制作用。计算的平均ID(50)、S和最大抑制百分率(MI)分别为：77、34和300nmokg(-1)和65+/-6、70+/-5和40+/-3%。鼻咽癌18688(100nmol·kg~(-1)，i.p.)具有抗痛敏作用。发病迅速(30分钟)，至少持续150分钟。预先给予HoE140(3-30nmol kg(-1)i.p)也能不同程度地抑制醋酸和ACh所致的扭体反应，其平均ID(50)、MI分别为6和9nmol kg(-1)和56+/-7和62+/-6%。3鼻咽癌18688(10-300nmol kg(-1)，i.p。)对福尔马林(2.5%)诱导的疼痛的两个阶段都有逐步抑制作用，其影响相对于福尔马林测试的第二阶段更有效。计算的平均ID(50)、S和MI对福尔马林致痛的第一和第二阶段的作用分别为>；300和60nmokg(-1)和20+/-3和60+/-5%。相同剂量的鼻咽癌18688还以剂量依赖的方式抑制福尔马林所致的足肿胀(MI为35+/-3%)。4当局部注射于小鼠足爪时，鼻咽癌18688(2，10和20nmoL/paw)没有激动剂活性。当与福尔马林-18688(2-20nmol/PAW)共同注射时，对福尔马林反应的两个时相均有明显的抑制作用，MI分别为40+/-3和33+/-2%。5NPC 18688(30-300nmol kg(-1))对足底注射辣椒素(1.6mug/paw)引起的伤害性反应有不同程度的抑制作用(40+/-2%)。然而，预先给药30min的鼻咽癌18688(高达300nmoL kg(-1)，i.p)，在甩尾和热板痛模型中没有明显的镇痛作用，也没有改变动物在旋转棒试验中的表现。6鼻咽癌18688对B-2受体有很强的选择性，和Hoe140一样，(1~100nmokg(-1)，i.p。)对缓激肽(BK，3moL/paw)诱导的小鼠足爪体积增加有不同程度的抑制作用，平均ID(50)S分别为61和6nmokg(-1)。此外，在100nmol·kg~(-1)的剂量下，NPC 18688可显著拮抗BK(3nmol/只)诱导的大鼠足肿胀，但对BK脱敏的Des-Arg(9)-BK(100nmoL/paw)所致的大鼠足肿胀无明显影响。鼻咽癌18688(210nmokg(-1))，如Hoe140(230nmokg(-1))皮下注射。30min前，完全解除BK(28nmol)诱导的降压作用，但不影响静脉注射所致平均动脉压的下降。注射ACh(2nmoL·kg(-1))。7这些结果表明，新开发的选择性伪肽B-2受体拮抗剂NPC 18688虽然不如现有的第二代B-2肽BK受体拮抗剂有效，但在几种小鼠伤害性感受模型中显示出局部和持久的全身性抗痛觉特性，使其成为研究BK和相关激肽参与生理和病理过程的有用工具。最后，这类新的选择性假肽B-2受体拮抗剂可能构成开发第三代有效且持久的口服活性非肽BK拮抗剂的新策略，这可能有助于临床治疗BK及其相关激动素的疾病。
1 The purpose of this study was to investigate the topical and systemic anti-hyperalgesic effect of the newly-developed pseudopeptide B-2 receptor antagonist, NPC 18688, in different models of nociception in mice.2 Given systemically 30 min beforehand, NPC 18688 (10-300 nmol kg(-1), i.p.) caused no agonist effect, but produced a dose-related and significant inhibition of abdominal constrictions caused by intraperitoneal injection of acetic acid (0.6%), acetylcholine (ACh, 4.5 mg kg(-1)) or kaolin (50 mg kg(-1)). The calculated mean ID(50)s and the percentages of maximal inhibitions (MI) for these effects were: 77, 34 and >300 nmol kg(-1) and 65+/-6, 70+/-5 and 40+/-3%, respectively. The anti-hyperalgesic effect of NPC 18688 (100 nmol kg(-1), i.p.) occurred rapidly (30 min) and lasted for at least 150 min. Hoe 140 (3-30 nmol kg(-1) i.p) given 30 min beforehand also inhibited, in a graded manner, acetic acid and ACh-induced writhing, with mean ID(50)s and MI of 6 and 9 nmol kg(-1) and 56+/-7 and 62+/-6%, respectively.3 NPC 18688 (10-300 nmol kg(-1), i.p.) caused a graded inhibition of both phases of formalin (2.5%)-induced pain, its effects being more potent in relation to the second phase of the formalin test. The calculated mean ID(50)s and the MI were >300 and 60 nmol kg(-1) and 20+/-3 and 60+/-5% against the first and second phases of formalin-induced nociception, respectively. NPC 18688 at the same doses also inhibited, in a dose-related manner, formalin-induced paw oedema (MI of 35+/-3%).4 When injected locally in the mouse paw, NPC 18688 (2, 10 and 20 nmol/paw) had no agonist activity. However, when co-injected with formalin NPC 18688 (2-20 nmol/paw), it produced significant inhibition of both phases of formalin response, with MI of 40+/-3 and 33+/-2%, respectively. NPC 18688 at 10 nmol/paw also significantly inhibited formalin-induced paw oedema (25+/-2%).5 Given intraperitoneally, NPC 18688 (30-300 nmol kg(-1)) determined a graded inhibition of the nociceptive response caused by intraplantar injection of capsaicin (1.6 mu g/paw) (40+/-2%). However, NPC 18688 (up to 300 nmol kg(-1), i.p.), given 30 min beforehand, had no significant analgesic effect when analyzed in the tail flick and in the hot plate pain models, nor did it change the performance of animals in the rota rod test.6 The action of NPC 18688 was quite selective for the B-2 receptor, and like Hoe 140, (1 to 100 nmol kg(-1), i.p.) it caused graded inhibition of bradykinin (BK, 3 mol/paw)-induced increase in mouse paw volume, with mean ID(50)s of 61 and 6 nmol kg(-1), respectively. In addition, at 100 nmol kg(-1) the dose at which NPC 18688 significantly antagonized BK (3 nmol)-mediated rat paw oedema in naive animals, it had no significant effect on des-Arg(9)-BK (100 nmol/paw)-induced oedema in paws that had been desensitized to BK. NPC 18688 (210 nmol kg(-1)), like Hoe 140 (230 nmol kg(-1)) given s.c. 30 min beforehand, completely abolished BK (28 nmol)-induced hypotension, without affecting the fall of mean arterial blood pressure induced by i.v. injection of ACh (2 nmol kg(-1)). Finally, NPC 18688 (1 mu M) did not affect ACh-mediated contraction in the guinea-pig ileum or toad rectus abdominii in vitro.7 These results demonstrate that the newly-developed and selective pseudopeptide B-2 receptor antagonist, NPC 18688, although less potent than the available second generation of B-2 peptide BK receptor antagonists, exhibits topical and long-lasting systemic anti-hyperalgesic properties when analysed in several models of nociception in mice, making it a useful tool for investigating the participation of BK and related kinins in physiological and pathological processes. Finally, this new class of selective pseudopeptide B-2 receptor antagonist may constitute a new strategy for developing the third generation of potent and long-lasting orally-active non-peptide BK antagonists, which may be useful for the management of clinical disorders involving BK and related kinins.