Department of Neurobiology and the Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Anesthesiology, Perioperative, and Pain Medicine, Department of Molecular and Cellular Physiology, and Department of Neurosurgery, Stanford Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
Neuron. 2018 Sep 19;99(6):1274-1288.e6. doi: 10.1016/j.neuron.2018.08.044.
Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation and nociceptor sensitization by inflammatory mediators. Finally, peripherally restricted KOR agonists selectively reduce pain and itch behaviors, as well as mechanical hypersensitivity associated with a surgical incision. These experiments provide a rationale for the use of peripherally restricted KOR agonists for therapeutic treatment.
初级传入神经已知受到κ 阿片受体 (KOR) 信号的抑制。然而，表达 KOR 的特定类型的感觉神经元仍不清楚。在这里，我们使用新开发的 KOR-cre 敲入等位基因、病毒追踪、单细胞 RT-PCR 和离体记录，表明 KOR 表达在几种初级传入纤维中：肽能感觉神经元的一个亚群，以及形成毛发周围的镰状或环状末梢的低阈值机械感受器。我们发现 KOR 在中枢发挥作用，抑制来自 KOR-cre 传入纤维在 I 和 III 层的兴奋性神经传递，这种作用可能是由于 KOR 介导的 Ca 流入抑制，我们在来自小鼠和人类的感觉神经元中观察到了这种抑制作用。在周围，KOR 信号通过炎症介质抑制神经源性炎症和伤害感受器敏化。最后，外周限制的 KOR 激动剂选择性地减少与手术切口相关的疼痛和瘙痒行为以及机械性敏感性。这些实验为使用外周限制的 KOR 激动剂进行治疗提供了依据。
