Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats
Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats
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DOI：
10.1002/ejp.1097
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发表时间：
2018-01-01
影响因子：
3.6
通讯作者：
Sors, A.
中科院分区：
文献类型：
--
作者：
Chaumette, T.;Chapuy, E.;Sors, A.
组胺H3受体主要表达在中枢神经系统神经元上，尤其是在伤害性通路上。方法在多种神经病理性疼痛模型上评价新型H3受体反向激动剂S 38093的抗伤害性作用，并与加巴喷丁和普瑞巴林进行比较。结果S 38093对健康大鼠的足底压力无明显影响，但在链脲佐菌素糖尿病神经病变模型上，急、慢性给药后均表现出明显的抗痛觉作用，仅慢性给药后才接受足爪压力测试。在奥沙利铂急性或反复给药致神经病变致冷尾浸泡模型上，受试S 38093急性给药各剂量组均表现出明显的抗寒超敏作用，冷超敏是奥沙利铂的主要副作用。在慢性给药(5天内每天2次)后，S 38093的作用增强，但在奥沙利铂模型中作用已最大，S 38093的作用动力学和作用大小与加巴喷丁和/或普伐他林相似。S 38093的抗伤害性作用可能部分是通过蓝斑的两种肾上腺素受体脱敏来实现的。结论S 38093具有减轻神经病理性疼痛的作用，值得临床应用，尤其是化疗药物所致的神经病理性疼痛。新的H3拮抗剂/反向激动剂S 38093在慢性给药后对神经病理性疼痛，尤其是对奥沙利铂所致的神经性疼痛有明显的止痛和止痛作用。S 38093对神经病理性疼痛的作用可能部分是通过蓝斑2种受体的脱敏来实现的。
BackgroundHistamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists.MethodsThe antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin.ResultsWhile S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by 2 adrenoreceptors desensitization in the locus coeruleus.ConclusionsThese results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain.SignificanceS 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by 2 receptors desensitization in the locus coeruleus.