The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats.
The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats.
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DOI：
10.1038/srep24591
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发表时间：
2016-04-18
影响因子：
4.6
通讯作者：
Zamanillo D
中科院分区：
文献类型：
--
作者：
Gris G;Portillo-Salido E;Aubel B;Darbaky Y;Deseure K;Vela JM;Merlos M;Zamanillo D
E-52862是一种选择性的σ1R拮抗剂，目前正在进行神经性疼痛的II期临床试验，是一种潜在的同类镇痛药。在这里，我们研究了单次和多次给药E-52862对几种神经性疼痛模型大鼠不同疼痛相关行为的影响：慢性缩窄性眼下神经（IoN）损伤后头（三叉）神经性疼痛的机械性异位痛，链脲霉素（STZ）诱导的糖尿病多发性神经病的机械性痛感，奥沙利铂（OX）诱导的多发性神经病的冷性异位痛。E-52862联合吗啡急性治疗可减轻离子手术或STZ给药后引起的机械超敏反应，而普瑞巴林则无此作用。在OX模型中，单次给药E-52862逆转了对冷刺激的超敏反应，类似于100 mg/kg加巴喷丁。有趣的是，在7天内，每天两次重复给药E-52862并没有诱导药效学耐受，但在所有三种模型中都增加了抗伤害感受作用。此外，如STZ和OX模型所示，每日重复使用E-52862治疗可减弱基线疼痛行为，这支持了对潜在疼痛产生机制的持续调节作用。这些临床前研究结果支持了σ1R在神经性疼痛中的作用，并扩展了选择性σ1R拮抗剂（如E-52862）用于慢性治疗头外神经性疼痛的潜力。
E-52862 is a selective σ1R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy, and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX models, repeated daily treatment with E-52862 attenuated baseline pain behaviours, which supports a sustained modifying effect on underlying pain-generating mechanisms. These preclinical findings support a role for σ1R in neuropathic pain and extend the potential for the use of selective σ1R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain.