Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and - Independent Mechanisms
Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and - Independent Mechanisms
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DOI：
10.3389/fphar.2019.00613
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发表时间：
2019-06-12
影响因子：
5.6
通讯作者：
Rafael Nieto, Francisco
中科院分区：
文献类型：
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作者：
Bravo-Caparros, Inmaculada;Perazzoli, Gloria;Rafael Nieto, Francisco
Sigma-1 (sigma(1)) 受体拮抗剂是神经病理性疼痛治疗的有前途的工具，但尚不清楚 sigma(1) 受体抑制是否能改善神经横断引起的神经病理性体征，其中病理生理机制和对药物治疗的反应与其他神经性疼痛模型不同。此外，sigma(1) 拮抗作用通过调节内源性阿片系统来改善炎性疼痛，但尚不清楚这是否发生在神经性疼痛期间。我们研究了 sigma(1) 抑制对小鼠免遭神经损伤 (SNI) 模型相关的疼痛性超敏反应的影响。野生型 (WT) 小鼠在 SNI 后出现明显的冷过敏（丙酮试验）、机械过敏（冯弗雷试验）和热过敏（哈格里夫斯试验）。 sigma(1) 受体敲除 (sigma(1)-KO) 小鼠没有出现冷异常性疼痛，并且机械异常性疼痛显着减少，尽管它们在 SNI 后出现热痛觉过敏。选择性 sigma(1) 受体拮抗剂 S1RA 的全身急性给药可减轻 WT 小鼠中所有三种类型的 SNI 诱导的超敏反应。 S1RA 的这些改善作用可通过给予 sigma(1) 激动剂 PRE-084 逆转，并且在 sigma(1)-KO 小鼠中不存在，表明 S1RA 诱导的作用具有选择性。阿片类拮抗剂纳洛酮及其外周限制性类似物纳洛酮甲硫氨酸可防止 S1RA 诱导的机械和热超敏反应，但不能防止冷异常性疼痛，表明阿片类药物依赖性和独立机制参与了这种 sigma(1) 拮抗剂的作用。在 10 天内每天两次重复施用 S1RA 可减少 SNI 引起的冷、机械和热超敏反应，且在治疗期间不会诱导镇痛耐受。这些作用在最后一次给药后 12 小时内观察到，此时血浆或脑中检测不到 S1RA，表明药效作用持久。这些数据表明，sigma(1) 拮抗作用对于治疗周围神经横断引起的神经性疼痛可能具有治疗价值。
Sigma-1 (sigma(1)) receptor antagonists are promising tools for neuropathic pain treatment, but it is unknown whether sigma(1) receptor inhibition ameliorates the neuropathic signs induced by nerve transection, in which the pathophysiological mechanisms and response to drug treatment differ from other neuropathic pain models. In addition, sigma(1) antagonism ameliorates inflammatory pain through modulation of the endogenous opioid system, but it is unknown whether this occurs during neuropathic pain. We investigated the effect of sigma(1) inhibition on the painful hypersensitivity associated with the spared nerve injury (SNI) model in mice. Wild-type (WT) mice developed prominent cold (acetone test), mechanical (von Frey test), and heat hypersensitivity (Hargreaves test) after SNI. sigma(1) receptor knockout (sigma(1)-KO) mice did not develop cold allodynia and showed significantly less mechanical allodynia, although they developed heat hyperalgesia after SNI. The systemic acute administration of the selective sigma(1) receptor antagonist S1RA attenuated all three types of SNI-induced hypersensitivity in WT mice. These ameliorative effects of S1RA were reversed by the administration of the sigma(1) agonist PRE-084, and were absent in sigma(1)-KO mice, indicating the selectivity of S1RA-induced effects. The opioid antagonist naloxone and its peripherally restricted analog naloxone methiodide prevented S1RA-induced effects in mechanical and heat hypersensitivity, but not in cold allodynia, indicating that opioid-dependent and -independent mechanisms are involved in the effects of this sigma(1) antagonist. The repeated administration of S1RA twice a day during 10 days reduced SNI-induced cold, mechanical, and heat hypersensitivity without inducing analgesic tolerance during treatment. These effects were observed up to 12 h after the last administration, when S1RA was undetectable in plasma or brain, indicating long-lasting pharmacodynamic effects. These data suggest that sigma(1) antagonism may have therapeutic value for the treatment of neuropathic pain induced by the transection of peripheral nerves.