Jarvis M F, Wessale J L, Zhu C Z, Lynch J J, Dayton B D, Calzadilla S V, Padley R J, Opgenorth T J, Kowaluk E A
Neurological and Urological Diseases Research and Metabolic Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6123, USA.
Eur J Pharmacol. 2000 Jan 24;388(1):29-35. doi: 10.1016/s0014-2999(99)00865-1.
Tactile allodynia, the enhanced perception of pain in response to normally non-painful stimulation, represents a common complication of diabetic neuropathy. The activation of endothelin ET(A) receptors has been implicated in diabetes-induced reductions in peripheral neurovascularization and concomitant endoneurial hypoxia. Endothelin receptor activation has also been shown to alter the peripheral and central processing of nociceptive information. The present study was conducted to evaluate the antinociceptive effects of the novel endothelin ET(A) receptor-selective antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats were injected with 75 mg/kg streptozotocin (i. p.), and drug effects were assessed 8-12 weeks following streptozotocin treatment to allow for stabilization of blood glucose levels (>/=240 mg/dl) and tactile allodynia thresholds (</=8.0 g). Systemic (i.p.) administration of ABT-627 (1 and 10 mg/kg) was found to produce a dose-dependent increase in tactile allodynia thresholds. A significant antinociceptive effect (40-50% increase in tactile allodynia thresholds, P<0.05) was observed at the dose of 10 mg/kg, i.p., within 0.5-2-h post-dosing. The antinociceptive effects of ABT-627 (10 mg kg(-1) day(-1), p.o.) were maintained following chronic administration of the antagonist in drinking water for 7 days. In comparison, morphine administered acutely at a dose of 8 mg/kg, i.p., produced a significant 90% increase in streptozotocin-induced tactile allodynia thresholds. The endothelin ET(B) receptor-selective antagonist, 2R-(4-propoxyphenyl)-4S-(1, 3-benzodioxol-5-yl)-1-(N-(2, 6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxy lic acid (A-192621; 20 mg/kg, i.p.), did not significantly alter tactile allodynia thresholds in streptozotocin-treated rats. Although combined i.p. administration of ABT-627 and A-192621 produced a significant, acute increase in tactile allodynia thresholds, this effect was significantly less than that produced by ABT-627 alone. These results indicate that the selective blockade of endothelin ET(A) receptors results in an attenuation of tactile allodynia in the streptozotocin-treated rat.
触觉异常性疼痛，即对正常无痛刺激产生增强的疼痛感知，是糖尿病性神经病变的常见并发症。内皮素ET(A)受体的激活与糖尿病引起的外周神经血管化减少及随之而来的神经内膜缺氧有关。内皮素受体激活还被证明会改变伤害性信息的外周和中枢处理过程。本研究旨在评估新型内皮素ET(A)受体选择性拮抗剂2R-(4-甲氧基苯基)-4S-(1,3-苯并二氧杂环戊烯-5-基)-1-(N,N-二(n-丁基)氨基羰基-甲基)-吡咯烷-3R-羧酸(ABT-627)在链脲佐菌素诱导的神经性疼痛糖尿病大鼠模型中的抗伤害感受作用。给大鼠腹腔注射75mg/kg链脲佐菌素，在链脲佐菌素治疗8-12周后评估药物效果，以使血糖水平稳定(≥240mg/dl)且触觉异常性疼痛阈值稳定(≤8.0g)。发现腹腔注射ABT-627(1和10mg/kg)可使触觉异常性疼痛阈值产生剂量依赖性增加。在腹腔注射10mg/kg剂量时，给药后0.5-2小时内观察到显著的抗伤害感受作用(触觉异常性疼痛阈值增加40-50%，P<0.05)。在饮水中慢性给予拮抗剂ABT-627(10mg kg-1 day-1，口服)7天后，其抗伤害感受作用得以维持。相比之下，腹腔注射8mg/kg剂量的吗啡可使链脲佐菌素诱导产生的触觉异常性疼痛阈值显著增加90%。内皮素ET(B)受体选择性拮抗剂2R-(4-丙氧基苯基)-4S-(1,3-苯并二氧杂环戊烯-5-基)-1-(N-(2,6-二乙基苯基)氨基羰基-甲基)-吡咯烷-3R-羧酸(A-1926,21；20mg/kg，腹腔注射)未显著改变链脲佐菌素治疗大鼠的触觉异常性疼痛阈值。尽管腹腔联合注射ABT-627和A-192621可使触觉异常性疼痛阈值产生显著的急性增加，但该作用明显小于单独使用ABT-627所产生的作用。这些结果表明，选择性阻断内皮素ET(A)受体可减轻链脲佐菌素治疗大鼠的触觉异常性疼痛。
