The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR), and also facilitates the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. In contrast to σ1R deficient mice, σ2R knockout mice developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Gly-ol]-encephalin (DAMGO) and β-endorphin increased in σ1R−/− mice and diminished in σ2R−/− mice. The analgesic effect of morphine was increased in σ2R−/− mice by treatment with S1RA. However, σ2R−/− mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55,212-2 and the α2-adrenergic receptor agonist clonidine. Therefore, while σR1 inhibits and σ2R facilitates MOR-mediated analgesia these receptors exchange their roles when regulating neuropathic pain perception. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies.

中文翻译：

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Sigma 2 受体促进和 Sigma 1 受体抑制μ-阿片受体介导的镇痛作用

Sigma-1 受体 (σ1R) 已成为一个有趣的药理学靶点，因为它抑制由 mu-阿片受体 (MOR) 介导的镇痛作用，并且还促进神经性疼痛的发展。基于这些发现，最近 Sigma-2 受体 (σ2R) 的克隆使我们研究了其作为阿片类药物镇痛和 σ2R 基因敲除小鼠疼痛超敏反应调节剂的潜在作用。与 σ1R 缺陷小鼠相比，σ2R 敲除小鼠在建立慢性收缩损伤引起的神经性疼痛后出现机械异常性疼痛，σ1R 拮抗剂 S1RA 缓解了这种疼痛。吗啡、[D-Ala、N-MePhe、Gly-ol]-脑啡肽 (DAMGO) 和 β-内啡肽的镇痛作用在 σ1R-/- 小鼠中增加，在 σ2R-/- 小鼠中减弱。通过用 S1RA 治疗，吗啡的镇痛作用在 σ2R-/- 小鼠中增加。然而，σ2R-/- 小鼠和野生型小鼠对 δ 受体激动剂 [D-Pen2,5]-脑啡肽 (DPDPE)、大麻素 1 型受体激动剂 WIN55,212-2 和 α2-肾上腺素能受体表现出相当的镇痛反应。受体激动剂可乐定。因此，虽然 σR1 抑制而 σ2R 促进 MOR 介导的镇痛，但这些受体在调节神经性疼痛感知时交换了它们的角色。我们的研究可能有助于确定新的药理学目标，以减轻疼痛感和改善阿片类药物解毒疗法。虽然 σR1 抑制和 σ2R 促进 MOR 介导的镇痛，但这些受体在调节神经性疼痛感知时交换了它们的角色。我们的研究可能有助于确定新的药理学目标，以减轻疼痛感和改善阿片类药物解毒疗法。虽然 σR1 抑制和 σ2R 促进 MOR 介导的镇痛，但这些受体在调节神经性疼痛感知时交换了它们的角色。我们的研究可能有助于确定新的药理学目标，以减轻疼痛感和改善阿片类药物解毒疗法。