PDF(Pubmed)
Abstract：
Cannabinoid CB2 agonists show therapeutic efficacy without unwanted CB1-mediated side effects. The G protein-biased CB2 receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB2 receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB2 agonists. Anti-allodynic effects of structurally distinct CB2 agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB2f/f mice and in mice lacking CB2 receptors in CX3CR1 expressing microglia/macrophages (CX3CR1CRE/+; CB2f/f), but were absent in mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB2f/f and CX3CR1CRE/+; CB2f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) AdvillinCRE/+; CB2f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB2f/f mice, but not AdvillinCRE/+; CB2f/f mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB2f/f or CX3CR1CRE/+; CB2f/f mice of either sex. Our findings have potential clinical implications.
摘要：
大麻素CB2激动剂显示出治疗功效而没有不需要的CB1介导的副作用。G蛋白偏向的CB2受体激动剂LY2828360减弱了雄性小鼠中化疗诱导的神经病性伤害感受的维持，并阻断了该模型中吗啡耐受性的发展。然而,参与这种现象的细胞类型是未知的，并且这种治疗模式是否在雌性小鼠中观察到从未被研究过。我们使用CB2受体的条件性缺失来确定介导CB2激动剂的抗痛觉异常和吗啡保留作用的细胞群。结构上不同的CB2激动剂（LY2828360和AM1710）的抗异常作用存在于紫杉醇治疗的CB2f/f小鼠和表达CX3CR1的小胶质细胞/巨噬细胞（CX3CR1CRE/；CB2f/f）中缺乏CB2受体的小鼠中，但在外周感觉神经元中缺乏CB2受体的小鼠中不存在（AdvillinCRE/；CB2f/f）。LY28282360的吗啡节制作用以性别二态的方式发生，出现在男性身上，但不是女性，mouse.LY2828360治疗（每天3mg/kg，i.p.x12天）阻断了雄性CB2f/f和CX3CR1CRE/+中吗啡耐受性的发展；CB2f/f小鼠已建立紫杉醇诱导的神经病变，但在雄性（或雌性）AdvillinCRE/+中不存在；CB2f/f小鼠。在紫杉醇治疗的雄性CB2f/f小鼠中，吗啡与低剂量LY2828360（每天0.1mg/kg，i.p.x6天）的联合给药逆转了吗啡耐受性，但不是AdvillinCRE/+；CB2f/f两种性别的小鼠。LY2828360（每天3mg/kg，i.p.x8天）延迟，但并没有阻止,在任一性别的CB2f/f或CX3CR1CRE/+;CB2f/f小鼠中紫杉醇诱导的机械性或冷异常性疼痛的发展。我们的发现具有潜在的临床意义。
