Département de physiologie et biophysique, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, QC, Canada.
Eur J Neurosci. 2010 Dec;32(11):1921-9. doi: 10.1111/j.1460-9568.2010.07466.x. Epub 2010 Oct 29.
We have shown that delta opioid receptor (DOPR)-mediated analgesia was enhanced in the complete Freund's adjuvant (CFA) model of inflammation. This effect is thought to originate from translocation of DOPR in the plasma membrane of dorsal root ganglia and spinal cord neurons. Among the putative mechanisms involved in the regulation of DOPR trafficking, an interaction with substance P (SP) in large dense-core vesicles has been described as an essential event for the externalization of DOPR. As we have previously observed that membrane DOPRs were upregulated in small- and medium-sized neurons under inflammatory pain conditions (whereas SP is mainly expressed by small dorsal root ganglia neurons), we raised the hypothesis that an SP-independent mechanism mediates DOPR trafficking and functional emergence in the CFA model. Therefore, we investigated the role of SP in DOPR-mediated analgesia by using preprotachykinin A (precursor of SP) knockout mice (PPTA(-/-) ) in the CFA model of inflammation. First, we confirmed that PPTA(-/-) mice are not expressing SP and have a similar level of CFA-induced inflammation as wildtype mice. Then, using the thermal plantar test, we found that an intrathecal injection of deltorphin II induced DOPR-mediated antihyperalgesia, which was not modified by the absence of SP (similar efficacy and potency in wildtype and PPTA(-/-) mice). We also observed similar analgesia of intrathecal deltorphin II for PPTA(-/-) and wildtype mice in the hot-water immersion tail-flick test. Consequently, our results suggest that SP is not essential for membrane insertion and for the functional emergence of DOPR.
我们已经表明，在完全弗氏佐剂（CFA）炎症模型中，δ 阿片受体（DOPR）介导的镇痛作用增强。这种效应被认为源自背根神经节和脊髓神经元质膜中 DOPR 的易位。在调节 DOPR 转运的假定机制中，与大致密核心囊泡中的物质 P（SP）相互作用已被描述为 DOPR 外化的必要事件。由于我们之前观察到在炎症性疼痛条件下（SP 主要由小背根神经节神经元表达），中小神经元中的膜 DOPR 上调，因此我们提出了一种假设，即一种 SP 独立的机制介导了 CFA 模型中 DOPR 的转运和功能出现。因此，我们通过使用前促皮素 A（SP 的前体）敲除小鼠（PPTA(-/-)）在 CFA 炎症模型中研究了 SP 在 DOPR 介导的镇痛中的作用。首先，我们证实 PPTA(-/-) 小鼠不表达 SP，并且具有与野生型小鼠相似的 CFA 诱导的炎症水平。然后，使用足底热板试验，我们发现鞘内注射 delta 啡肽 II 诱导 DOPR 介导的抗痛觉过敏，而 SP 的缺失并未改变（在野生型和 PPTA(-/-) 小鼠中具有相似的效力和效价）。我们还观察到鞘内 delta 啡肽 II 在 PPTA(-/-)和野生型小鼠的热水浸尾 flick 试验中产生相似的镇痛作用。因此，我们的结果表明 SP 对于膜插入和 DOPR 的功能出现不是必需的。
