Jin Daozhong, Chen Hong, Huang Yuying, Chen Shao-Rui, Pan Hui-Lin
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Neuropharmacology. 2022 Oct 1;217:109202. doi: 10.1016/j.neuropharm.2022.109202. Epub 2022 Jul 31.
δ-Opioid receptors (DORs, encoded by the Oprd1 gene) are expressed throughout the peripheral and central nervous system, and DOR stimulation reduces nociception. Previous studies suggest that DORs promote the development of analgesic tolerance of μ-opioid receptor (MOR) agonists. It is uncertain whether DORs expressed in primary sensory neurons are involved in regulating chronic pain and MOR agonist-induced tolerance. In this study, we generated Oprd1 conditional knockout (Oprd1-cKO) mice by crossing Advillin-Cre mice with Oprd1-floxed mice. DOR expression in the dorsal root ganglion was diminished in Oprd1-cKO mice. Systemic or intrathecal injection of the DOR agonist SNC-80 produced analgesia in wild-type (WT), but not Oprd1-cKO, mice. In contrast, intracerebroventricular injection of SNC-80 produced a similar analgesic effect in WT and Oprd1-cKO mice. However, morphine-induced analgesia, hyperalgesia, or analgesic tolerance did not differ between WT and Oprd1-cKO mice. Compared with WT mice, Oprd1-cKO mice showed increased mechanical and heat hypersensitivity after nerve injury or tissue inflammation. Furthermore, blocking DORs with naltrindole increased nociceptive sensitivity induced by nerve injury or tissue inflammation in WT, but not Oprd1-cKO, mice. In addition, naltrindole potentiated glutamatergic input from primary afferents to spinal dorsal horn neurons increased by nerve injury or CFA in WT mice; this effect was absent in Oprd1-cKO mice. Our findings indicate that DORs in primary sensory neurons are critically involved in the analgesic effect of DOR agonists but not morphine-induced analgesic tolerance. Presynaptic DORs at primary afferent central terminals constitutively inhibit inflammatory and neuropathic pain by restraining glutamatergic input to spinal dorsal horn neurons.
δ-阿片受体（DORs，由Oprd1基因编码）在周围和中枢神经系统中均有表达，刺激DOR可减轻伤害感受。先前的研究表明，DORs会促进μ-阿片受体（MOR）激动剂镇痛耐受性的形成。目前尚不清楚初级感觉神经元中表达的DORs是否参与调节慢性疼痛和MOR激动剂诱导的耐受性。在本研究中，我们通过将Advillin-Cre小鼠与Oprd1基因 floxed 小鼠杂交，培育出了Oprd1条件性敲除（Oprd1-cKO）小鼠。Oprd1-cKO小鼠背根神经节中的DOR表达减少。全身或鞘内注射DOR激动剂SNC-80可使野生型（WT）小鼠产生镇痛作用，但对Oprd1-cKO小鼠无效。相比之下，脑室内注射SNC-80在WT和Oprd1-cKO小鼠中产生的镇痛效果相似。然而，WT和Oprd1-cKO小鼠在吗啡诱导的镇痛、痛觉过敏或镇痛耐受性方面并无差异。与WT小鼠相比，Oprd1-cKO小鼠在神经损伤或组织炎症后表现出机械性和热超敏反应增强。此外，用纳曲吲哚阻断DORs可增加WT小鼠因神经损伤或组织炎症诱导的伤害性敏感性，但对Oprd1-cKO小鼠无效。此外，纳曲吲哚增强了WT小鼠中因神经损伤或弗氏完全佐剂（CFA）导致的初级传入纤维到脊髓背角神经元的谷氨酸能输入增加；而在Oprd1-cKO小鼠中未观察到这种效应。我们的研究结果表明，初级感觉神经元中的DORs对DOR激动剂的镇痛作用至关重要，但对吗啡诱导的镇痛耐受性并无影响。初级传入中枢终末的突触前DORs通过抑制谷氨酸能输入到脊髓背角神经元，从而持续抑制炎症性和神经性疼痛。
