Department of Anesthesiology, 26367Nippon Medical School, Bunkyo-ku, Japan.
Department of Pharmacology, 26367Nippon Medical School, Bunkyo-ku, Japan.
Mol Pain. 2021 Jan-Dec;17:17448069211058004. doi: 10.1177/17448069211058004.
Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes severe neuropathic pain typically encompassing cold allodynia and long-lasting mechanical allodynia. Endothelin has been shown to modulate nociceptive transmission in a variety of pain disorders. However, the action of endothelin varies greatly depending on many variables, including pain causes, receptor types (endothelin type A (ET) and B (ET) receptors) and organs (periphery and spinal cord). Therefore, in this study, we investigated the role of endothelin in a Sprague-Dawley rat model of oxaliplatin-induced neuropathic pain. Intraperitoneal administration of bosentan, a dual ET/ET receptor antagonist, effectively blocked the development or prevented the onset of both cold allodynia and mechanical allodynia. The preventive effects were exclusively mediated by ET receptor antagonism. Intrathecal administration of an ET receptor antagonist prevented development of long-lasting mechanical allodynia but not cold allodynia. In marked contrast, an intraplantar ET receptor antagonist had a suppressive effect on cold allodynia but only had a partial and transient effect on mechanical allodynia. In conclusion, ET receptor antagonism effectively prevented long-lasting mechanical allodynia through spinal and peripheral actions, while cold allodynia was prevented through peripheral actions.
奥沙利铂是一种基于铂的化疗药物，常引起严重的神经病理性疼痛，通常包括冷感觉异常和持久的机械性感觉异常。内皮素已被证明可调节多种疼痛疾病中的伤害性传递。然而，内皮素的作用因许多变量而异，包括疼痛原因、受体类型（内皮素 A (ET) 和 B (ET) 受体）和器官（外周和脊髓）。因此，在这项研究中，我们研究了内皮素在奥沙利铂诱导的神经病理性疼痛 Sprague-Dawley 大鼠模型中的作用。腹腔内给予内皮素 A 和内皮素 B 双重受体拮抗剂博来霉素可有效阻断冷感觉异常和机械性感觉异常的发展或预防其发作。预防作用完全是通过内皮素受体拮抗作用介导的。鞘内给予内皮素受体拮抗剂可预防持久的机械性感觉异常的发展，但不能预防冷感觉异常。相比之下，足底内皮素受体拮抗剂对冷感觉异常有抑制作用，但对机械性感觉异常只有部分和短暂的作用。总之，内皮素受体拮抗作用通过脊髓和外周作用有效预防持久的机械性感觉异常，而冷感觉异常则通过外周作用预防。
