Lin Xiaoyan, Xu Zhili, Carey Lawrence, Romero Julian, Makriyannis Alexandros, Hillard Cecilia J, Ruggiero Elizabeth, Dockum Marilyn, Houk George, Mackie Ken, Albrecht Phillip J, Rice Frank L, Hohmann Andrea G
Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States.
Program in Neuroscience, Indiana University, Bloomington, IN, United States.
Pain. 2022 May 1;163(5):834-851. doi: 10.1097/j.pain.0000000000002502.
CB2 cannabinoid receptors (CB2) are a promising therapeutic target that lacks unwanted side effects of CB1 activation. However, the cell types expressing CB2 that mediate these effects remain poorly understood. We used transgenic mice with CB2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express CB2 and suppress neuropathic nociception in a mouse model of chemotherapy-induced peripheral neuropathy. Structurally distinct CB2 agonists (AM1710 and LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia in CB2EGFP reporter mice with established neuropathy. Antiallodynic effects of AM1710 were blocked by SR144528, a CB2 antagonist with limited CNS penetration. Intraplantar AM1710 administration suppressed paclitaxel-induced neuropathic nociception in CB2EGFP but not CB2 knockout mice, consistent with a local site of antiallodynic action. mRNA expression levels of the anti-inflammatory cytokine interleukin-10 were elevated in the lumbar spinal cord after intraplantar AM1710 injection along with the proinflammatory cytokine tumor necrosis factor alpha and chemokine monocyte chemoattractant protein-1. CB2EGFP, but not wildtype mice, exhibited anti-GFP immunoreactivity in the spleen. However, the anti-GFP signal was below the threshold for detection in the spinal cord and brain of either vehicle-treated or paclitaxel-treated CB2EGFP mice. EGFP fluorescence was coexpressed with CB2 immunolabeling in stratified patterns among epidermal keratinocytes. EGFP fluorescence was also expressed in dendritic cells in the dermis, Langerhans cells in the epidermis, and Merkel cells. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception.
CB2大麻素受体（CB2）是一个很有前景的治疗靶点，不会产生激活CB1所带来的不良副作用。然而，介导这些效应的表达CB2的细胞类型仍知之甚少。我们使用了CB2启动子驱动增强型绿色荧光蛋白（EGFP）表达的转基因小鼠，来研究在化疗诱导的周围神经病变小鼠模型中表达CB2并抑制神经性疼痛的细胞类型。结构不同的CB2激动剂（AM1710和LY2828360）可抑制已患神经病变的CB2EGFP报告基因小鼠中紫杉醇诱导的机械性和冷觉异常性疼痛。AM1710的抗痛觉过敏作用被SR144528阻断，SR144528是一种中枢神经系统穿透性有限的CB2拮抗剂。足底注射AM1710可抑制CB2EGFP小鼠而非CB2基因敲除小鼠中紫杉醇诱导的神经性疼痛，这与抗痛觉过敏作用的局部位点一致。足底注射AM1710后，腰椎脊髓中抗炎细胞因子白细胞介素-10以及促炎细胞因子肿瘤坏死因子α和趋化因子单核细胞趋化蛋白-1的mRNA表达水平升高。CB2EGFP小鼠而非野生型小鼠在脾脏中表现出抗GFP免疫反应性。然而，在接受载体处理或紫杉醇处理的CB2EGFP小鼠的脊髓和脑中，抗GFP信号低于检测阈值。EGFP荧光与CB2免疫标记在表皮角质形成细胞中呈分层模式共表达。EGFP荧光也在真皮中的树突状细胞、表皮中的朗格汉斯细胞和默克尔细胞中表达。对EGFP信号的定量分析显示，紫杉醇处理后表皮中的朗格汉斯细胞动态增加。我们的研究表明，在先前未被认识的皮肤细胞群体中表达的CB2是抑制化疗诱导的神经性疼痛的潜在靶点。
