Center for Translational Pain Medicine, Department of Anesthesiology, and Department of Neurobiology, Duke University Medical Center, Durham, NC, United States.
Department of Cell Biology, Duke University Medical Center, Durham, NC, United States.
Pain. 2023 Jun 1;164(6):1340-1354. doi: 10.1097/j.pain.0000000000002824. Epub 2022 Nov 14.
Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1 n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.
专门的促解决介质 (SPM) 在病理性疼痛的动物模型中表现出强大的镇痛作用。SPM 在急性和慢性瘙痒中的作用目前尚不清楚。最近，n-3 二十二碳五烯酸 (DPA) 被发现是几种新型 SPM 家族生物合成的底物，而 3-氧代-PD1 n-3 DPA (3-oxa-PD1) 是 n-3 DPA 衍生的保护素 D1 (PD1) 的氧化抗性代谢稳定类似物。在本文中，我们证明了 3-oxa-PD1 可有效减轻小鼠模型中的急性和慢性瘙痒。鞘内注射 3-oxa-PD1（100ng）可减轻组胺、氯喹或吗啡诱导的急性瘙痒。此外，鞘内注射 3-oxa-PD1 还可有效减轻由皮肤 T 细胞淋巴瘤 (CTCL)、二硝基氟苯引起的过敏性接触性皮炎和咪喹莫特诱导的银屑病引起的慢性瘙痒。肿瘤内注射 3-oxa-PD1 也可抑制 CTCL 诱导的慢性瘙痒。引人注目的是，在 1 周鞘内注射 3-oxa-PD1 治疗后，止痒作用可持续数周。全细胞记录显示 CTCL 小鼠脊髓背角 (SDH) 神经元的兴奋性突触后电流显著增加，但这一增加被 3-oxa-PD1 阻断。3-oxa-PD1 进一步增加 CTCL 小鼠 SDH 神经元的抑制性突触后电流。皮肤 T 细胞淋巴瘤增加了由星形胶质细胞产生的瘙痒介质脂联素-2 (LCN2) 的脊髓水平。3-oxa-PD1 抑制 CTCL 小鼠的 LCN2 产生和星形胶质细胞的 LCN2 分泌。最后，鞘内注射 3-oxa-PD1 可减轻 CTCL 诱导的焦虑。我们的研究结果表明，3-oxa-PD1 通过调节兴奋性或抑制性突触传递和星形胶质细胞 LCN2 产生，有力地抑制急性和慢性瘙痒。因此，稳定的 SPM 类似物如 3-oxa-PD1 可能对治疗不同皮肤损伤引起的瘙痒有用。
