Deng Liting, Guindon Josée, Cornett Benjamin L, Makriyannis Alexandros, Mackie Ken, Hohmann Andrea G
Program in Neuroscience, Indiana University, Bloomington, Indiana; Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana; Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, Indiana.
Program in Neuroscience, Indiana University, Bloomington, Indiana; Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana.
Biol Psychiatry. 2015 Mar 1;77(5):475-87. doi: 10.1016/j.biopsych.2014.04.009. Epub 2014 Apr 25.
Mixed cannabinoid receptor 1 and 2 (CB1 and CB2) agonists such as Δ(9)-tetrahydrocannabinol (Δ(9)-THC) can produce tolerance, physical withdrawal, and unwanted CB1-mediated central nervous system side effects. Whether repeated systemic administration of a CB2-preferring agonist engages CB1 receptors or produces CB1-mediated side effects is unknown.
We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB2-preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid Δ(9)-THC. We also explored the site and possible mechanism of action of AM1710.
Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB1KO, CB2KO, and WT mice. Both AM1710 and Δ(9)-THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ(9)-THC, chronic administration of AM1710 did not engage CB1 activity or produce antinociceptive tolerance, CB1-mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB2KO mice and WT mice receiving the CB2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB2KO mice, implicating a possible role for spinal CB2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-α and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice.
Our results highlight the potential of prolonged use of CB2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB1-mediated side effects.
混合大麻素受体1和2（CB1和CB2）激动剂，如Δ(9)-四氢大麻酚（Δ(9)-THC），可产生耐受性、身体戒断反应以及不良的CB1介导的中枢神经系统副作用。重复全身给予CB2选择性激动剂是否会激活CB1受体或产生CB1介导的副作用尚不清楚。
我们在紫杉醇诱导的化疗性神经病变模型中，使用CB1基因敲除（CB1KO）、CB2基因敲除（CB2KO）和野生型（WT）小鼠，评估了重复给予CB2选择性激动剂AM1710的抗痛觉过敏疗效、可能的耐受性和拟大麻效应副作用。并与典型的经典大麻素Δ(9)-THC进行了比较。我们还探究了AM1710的作用位点和可能的作用机制。
在CB1KO、CB2KO和WT小鼠中，紫杉醇诱导的机械性和冷痛觉过敏发展程度相当。AM1710和Δ(9)-THC均能抑制WT小鼠已建立的紫杉醇诱导的痛觉过敏。与Δ(9)-THC不同，慢性给予AM1710不会激活CB1活性或产生抗伤害感受耐受性、CB1介导的大麻素戒断反应、体温过低或运动功能障碍。在CB2KO小鼠和全身或鞘内给予CB2拮抗剂AM630的WT小鼠中，全身给予AM1710无抗痛觉过敏疗效。鞘内给予AM1710也可减轻WT小鼠紫杉醇诱导的痛觉过敏，但对CB2KO小鼠无效，这表明脊髓CB2受体可能在AM1710的抗痛觉过敏疗效中起作用。最后，急性和慢性给予AM1710均可降低紫杉醇处理的WT小鼠腰脊髓中肿瘤坏死因子-α和单核细胞趋化蛋白1的信使核糖核酸水平。
我们的结果突出了长期使用CB2激动剂治疗化疗诱导的痛觉过敏的潜力，其治疗比率良好，表现为疗效持续且无耐受性、身体戒断反应或CB1介导的副作用。
