Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Neurosci. 2012 May 16;32(20):7091-101. doi: 10.1523/JNEUROSCI.0403-12.2012.
Painful peripheral neuropathy is a dose-limiting complication of chemotherapy. Cisplatin produces a cumulative toxic effect on peripheral nerves, and 30-40% of cancer patients receiving this agent experience pain. By modeling cisplatin-induced hyperalgesia in mice with daily injections of cisplatin (1 mg/kg, i.p.) for 7 d, we investigated the anti-hyperalgesic effects of anandamide (AEA) and cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), an inhibitor of AEA hydrolysis. Cisplatin-induced mechanical and heat hyperalgesia were accompanied by a decrease in the level of AEA in plantar paw skin. No changes in motor activity were observed after seven injections of cisplatin. Intraplantar injection of AEA (10 μg/10 μl) or URB597 (9 μg/10 μl) transiently attenuated hyperalgesia through activation of peripheral CB₁ receptors. Co-injections of URB597 (0.3 mg/kg daily, i.p.) with cisplatin decreased and delayed the development of mechanical and heat hyperalgesia. The effect of URB597 was mediated by CB₁ receptors since AM281 (0.33 mg/kg daily, i.p.) blocked the effect of URB597. Co-injection of URB597 also normalized the cisplatin-induced decrease in conduction velocity of Aα/Aβ-fibers and reduced the increase of ATF-3 and TRPV1 immunoreactivity in dorsal root ganglion (DRG) neurons. Since DRGs are a primary site of toxicity by cisplatin, effects of cisplatin were studied on cultured DRG neurons. Incubation of DRG neurons with cisplatin (4 μg/ml) for 24 h decreased the total length of neurites. URB597 (100 nM) attenuated these changes through activation of CB₁ receptors. Collectively, these results suggest that pharmacological facilitation of AEA signaling is a promising strategy for attenuating cisplatin-associated sensory neuropathy.
痛性周围神经病变是化疗的剂量限制并发症。顺铂对周围神经产生累积毒性作用，接受该药物治疗的 30-40%的癌症患者会出现疼痛。通过对每天接受顺铂（1mg/kg，腹腔注射）7d 处理的小鼠建模，研究了大麻素（AEA）和环己基氨基甲酸 3'-氨基甲酰联苯-3-基酯（URB597）对痛觉过敏的抗作用，URB597 是 AEA 水解的抑制剂。顺铂诱导的机械和热痛觉过敏伴随着足底皮肤中 AEA 水平的降低。在接受七次顺铂注射后，没有观察到运动活动的变化。足底注射 AEA（10μg/10μl）或 URB597（9μg/10μl）通过激活外周 CB₁ 受体短暂减轻痛觉过敏。URB597（0.3mg/kg，每天腹腔注射）与顺铂共同注射可降低和延迟机械和热痛觉过敏的发展。URB597 的作用是通过 CB₁ 受体介导的，因为 AM281（0.33mg/kg，每天腹腔注射）阻断了 URB597 的作用。URB597 的共同注射还使顺铂诱导的 Aα/Aβ 纤维传导速度降低和背根神经节（DRG）神经元中 ATF-3 和 TRPV1 免疫反应性增加正常化。由于 DRG 是顺铂毒性的主要部位，因此研究了顺铂对培养的 DRG 神经元的影响。将 DRG 神经元与顺铂（4μg/ml）孵育 24h 会减少轴突的总长度。URB597（100nM）通过激活 CB₁ 受体减弱了这些变化。总之，这些结果表明，药理学增强 AEA 信号转导是减轻顺铂相关感觉神经病变的有前途的策略。
