Pharmacological Modulation of the Sigma 1 Receptor and the Treatment of Pain
Pharmacological Modulation of the Sigma 1 Receptor and the Treatment of Pain
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DOI：
10.1007/978-3-319-50174-1_8
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Miguel Vela, Jose
中科院分区：
文献类型：
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作者：
Merlos, Manuel;Burgueno, Javier;Miguel Vela, Jose
迫切需要新的止痛药通过新的作用机制发挥作用，这可能会增加现有疗法的疗效，并减少其有害的影响。目前的临床前证据支持Sigma-1受体(Sigma R-1)在伤害性感受中的调节作用，主要基于Sigma R-1基因敲除小鼠的疼痛减弱表型以及Sigma R-1拮抗剂对不同病因疼痛的抗伤害感觉作用。Sigma R-1在中枢和外周(特别是背根神经节)的不同痛区高度表达，并相互作用并调节不同受体和离子通道的功能。Sigma R-1的拮抗作用导致脊髓内疼痛信号的放大减少(中枢敏化)，但最近的数据也支持在外周发挥作用。Sigma R-1拮抗剂一直被证明对神经性疼痛有效，但也对其他类型的疼痛有效，包括炎性疼痛、口面部疼痛、内脏疼痛和手术后疼痛。除了单独作用外，当与阿片类药物联合使用时，Sigma R-1拮抗剂可以增强阿片类药物的镇痛作用，但不会产生阿片类药物引起的不良影响。有趣的是，与阿片类药物不同的是，Sigma R-1拮抗剂不会改变正常的感觉、机械和热敏感阈值，但它们在敏化条件下发挥抗过敏作用，使伤害阈值恢复到正常值。因此，Sigma R-1拮抗剂并不是严格意义上的止痛药；它们是当系统在长时间的伤害性刺激或持续的异常传入输入(例如，继发于神经损伤)后被敏化时起作用的止痛药和抗痛敏药物。这些都是独特的特征，使Sigma R-1拮抗剂能够在慢性疼痛等病理生理条件下发挥调节作用。
There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy with respect to existing therapies and reduce their unwanted effects. Current preclinical evidence supports the modulatory role of sigma-1 receptors (sigma R-1) in nociception, mainly based on the pain-attenuated phenotype of sigma R-1 knockout mice and on the antinociceptive effect exerted by sigma R-1 antagonists on pains of different etiologies. sigma R-1 is highly expressed in different pain areas of the CNS and the periphery (particularly dorsal root ganglia), and interacts and modulates the functionality of different receptors and ion channels. The antagonism of sigma R-1 leads to decreased amplification of pain signaling within the spinal cord (central sensitization), but recent data also support a role at the periphery. sigma R-1 antagonists have consistently demonstrated efficacy in neuropathic pain, but also in other types of pain including inflammatory, orofacial, visceral, and post-operative pain. Apart from acting alone, when combined with opioids, sigma R-1 antagonists enhance opioid analgesia but not opioid-induced unwanted effects. Interestingly, unlike opioids, sigma R-1 antagonists do not modify normal sensory mechanical and thermal sensitivity thresholds but they exert antihypersensitive effects in sensitizing conditions, enabling the reversal of nociceptive thresholds back to normal values. Accordingly, sigma R-1 antagonists are not strictly analgesics; they are antiallodynic and antihyperalgesic drugs acting when the system is sensitized following prolonged noxious stimulation or persistent abnormal afferent input (e.g., secondary to nerve injury). These are distinctive features allowing sigma R-1 antagonists to exert a modulatory effect specifically in pathophysiological conditions such as chronic pain.