Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain
Characterization of Sigma 1 Receptor Antagonist CM-304 and Its Analog, AZ-66: Novel Therapeutics Against Allodynia and Induced Pain
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DOI：
10.3389/fphar.2019.00678
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发表时间：
2019-06-14
影响因子：
5.6
通讯作者：
McLaughlin, Jay P.
中科院分区：
文献类型：
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作者：
Cirino, Thomas J.;Eans, Shainnel O.;McLaughlin, Jay P.
Sigma-1受体（SIR）和sigma-2受体（S2R）可以在没有阿片类药物的情况下调节伤害感受，为治疗疼痛提供了一个有希望的治疗靶点。本研究的目的是研究两种新型sigma受体拮抗剂CM-304及其类似物非选择性S1R/S2R拮抗剂AZ-66的体内镇痛和抗异动活性。以雄性小鼠作为神经性疼痛模型，评估了热、化学或炎症性疼痛的抑制作用，以及慢性神经收缩损伤（CCI）和顺铂暴露引起的异常性疼痛。两种西格玛受体拮抗剂剂量依赖性（10-45 mg/kg, i.p）减轻了CCI和顺铂神经性疼痛模型中的异位性疼痛，在较高剂量下与对照镇痛药加巴喷丁（50 mg/kg, i.p）的效果相当，尽管AZ-66显示出更长的作用时间。CM-304和AZ-66在扭体试验中产生的抗痛作用[分别为0.48（0.09-1.82）和2.31 (1.02-4.81)mg/kg, i.p]相当于吗啡[1.75 (0.31-7.55)mg/kg, i.p]。同样，在炎症性疼痛的福尔马林爪实验中，使用任一种西格玛受体拮抗剂的预处理（i.p）剂量依赖性地产生抗痛感。然而，CM-304 [17.5 (12.7-25.2) mg/kg, i.p)和AZ-66 [11.6 (8.29-15.6) mg/kg, i.p]在55℃温水退尾试验中的效果不如吗啡[3.87 (2.85-5.18)mg/kg, i.p]。AZ-66在旋转实验和条件厌恶实验中表现出适度的镇静作用，CM-304在条件反射实验中没有显著的镇静作用。总的来说，这些结果表明S1R选择性拮抗剂CM-304比现有的治疗方法产生抗痛觉和抗异常痛觉的副作用更少，支持使用S1R拮抗剂作为慢性疼痛的潜在治疗方法。
Sigma-1 receptors (SIR) and sigma-2 receptors (S2R) may modulate nociception without the liabilities of opioids, offering a promising therapeutic target to treat pain. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity of two novel sigma receptor antagonists, the S1R-selective CM-304 and its analog the non-selective S1R/S2R antagonist AZ-66. Inhibition of thermal, induced chemical or inflammatory pain, as well as the allodynia resulting from chronic nerve constriction injury (CCI) and cisplatin exposure as models of neuropathic pain were assessed in male mice. Both sigma receptor antagonists dose-dependently (10-45 mg/kg, i.p.) reduced allodynia in the CCI and cisplatin neuropathic pain models, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg, i.p.), although AZ-66 demonstrated a much longer duration of action. Both CM-304 and AZ-66 produced antinociception in the writhing test [0.48 (0.09-1.82) and 2.31 (1.02-4.81) mg/kg, i.p., respectively] equivalent to morphine [1.75 (0.31-7.55) mg/kg, i.p.]. Likewise, pretreatment (i.p.) with either sigma-receptor antagonist dose-dependently produced antinociception in the formalin paw assay of inflammatory pain. However, CM-304 [17.5 (12.7-25.2) mg/kg, i.p.) and AZ-66 [11.6 (8.29-15.6) mg/kg, i.p.) were less efficacious than morphine [3.87 (2.85-5.18) mg/kg, i.p.] in the 55 degrees C warm-water tail-withdrawal assay. While AZ-66 exhibited modest sedative effects in a rotarod assay and conditioned place aversion, CM-304 did not produce significant effects in the place conditioning assay. Overall, these results demonstrate the S1R selective antagonist CM-304 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, supporting the use of S1R antagonists as potential treatments for chronic pain.