Université Clermont Auvergne, Inserm U1107 Neuro-Dol, Pharmacologie Fondamentale et Clinique de la Douleur, Clermont-Ferrand, France.
Neuropsychopharmacology and Psychobiology Research Laboratory, University of Cádiz, Spain.
Eur J Pain. 2018 Jan;22(1):127-141. doi: 10.1002/ejp.1097. Epub 2017 Sep 6.
Histamine 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.
The 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.
While 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 5 days) 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 α2 adrenoreceptors desensitization in the locus coeruleus.
These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain.
S 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 α2 receptors desensitization in the locus coeruleus.
组胺 H3 受体主要表达于中枢神经系统神经元，特别是在痛觉通路上。这些受体在疼痛处理中的潜在作用已被 H3 受体反向激动剂所证实。
我们评估了新型 H3 受体反向激动剂 S 38093 在几种大鼠神经病理性疼痛模型中的抗伤害作用，并与加巴喷丁和普瑞巴林进行了比较。
S 38093 对健康大鼠的足底压力诱发的发声阈值没有影响，但在链脲佐菌素诱导的糖尿病（STZ）神经病变模型中，无论是急性还是慢性给药后，以及在慢性缩窄性损伤（CCI）模型中，只有在慢性给药后，进行足底压力测试时，S 38093 均显示出显著的抗痛觉过敏作用。在急性或重复给予奥沙利铂诱导的神经病变模型中，急性 S 38093 给药在所有测试剂量下均显示出显著的冷感觉异常缓解作用，冷感觉异常是奥沙利铂在患者中的主要副作用。在 CCI 和 STZ 模型中，S 38093 的作用在慢性给药后（即连续 5 天每天给药 2 次）增加，而在奥沙利铂模型中，其作用从首次给药时已经达到最大。S 38093 的作用动力学和大小与加巴喷丁和/或普瑞巴林相似。最后，S 38093 的抗伤害作用可能部分通过蓝斑去甲肾上腺素能受体脱敏介导。
这些结果突出了 S 38093 缓解神经病理性疼痛的潜力，特别是在化疗药物诱导的神经病理性疼痛中，值得进行临床试验。
新型 H3 拮抗剂/反向激动剂 S 38093 对神经病理性疼痛具有抗感觉异常和抗痛觉过敏作用，尤其是在慢性给药后奥沙利铂诱导的神经病变中。S 38093 在神经病理性疼痛中的这种作用可能部分通过蓝斑去甲肾上腺素能受体脱敏介导。
