Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, 53127, Bonn, Germany.
Sci Rep. 2018 Jul 17;8(1):10827. doi: 10.1038/s41598-018-28507-6.
Neuropathic pain typically appears in a region innervated by an injured or diseased nerve and, in some instances, also on the contralateral side. This so-called mirror image pain is often observed in mice lacking CB2 receptors after sciatic nerve injury, but the underlying mechanisms for this phenotype largely remain unclear. Here we focused on peripheral leptin signaling, which modulates neuropathic pain development and interacts with the endocannabinoid system. Leptin production is induced at the site of nerve injury in CB2-deficient mice (CB2-KO) mice and wild type controls (WT). However, induction of leptin receptor expression was only observed in the injured nerve of CB2-KO mice. This was paralleled by a stimulation of the leptin receptor-downstream STAT3 signaling and an infiltration of F4/80-positive macrophages. Interestingly, an upregulation of leptin receptor expression STAT3 activity and macrophage infiltration was also observed on the non-injured nerve of CB2-KO mice thus reflecting the mirror image pain in CB2-KO animals. Importantly, perineurally-administered leptin-neutralizing antibodies reduced mechanical hyperalgesia, blocked mirror image pain and inhibited the recruitment of F4/80-positive macrophages. These results identify peripheral leptin signaling as an important modulator of CB2 signaling in neuropathic pain.
神经病理性疼痛通常出现在受损伤或患病神经支配的区域，在某些情况下，也会出现在对侧。在坐骨神经损伤后的 CB2 受体缺失的小鼠中，经常观察到这种所谓的镜像疼痛，但这种表型的潜在机制在很大程度上仍不清楚。在这里，我们专注于外周瘦素信号，它调节神经病理性疼痛的发展，并与内源性大麻素系统相互作用。在 CB2 缺失型（CB2-KO）小鼠和野生型对照（WT）的神经损伤部位诱导产生瘦素。然而，只有在 CB2-KO 小鼠的损伤神经中观察到瘦素受体表达的诱导。这与瘦素受体下游 STAT3 信号的刺激和 F4/80 阳性巨噬细胞的浸润平行。有趣的是，在 CB2-KO 小鼠的非损伤神经中也观察到瘦素受体表达、STAT3 活性和巨噬细胞浸润的上调，从而反映了 CB2-KO 动物的镜像疼痛。重要的是，鞘内给予瘦素中和抗体可减轻机械性痛觉过敏，阻断镜像疼痛，并抑制 F4/80 阳性巨噬细胞的募集。这些结果表明，外周瘦素信号是神经病理性疼痛中 CB2 信号的重要调节剂。
