Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Neurosci. 2012 Sep 12;32(37):12735-43. doi: 10.1523/JNEUROSCI.0130-12.2012.
The amplitude of the depolarization-evoked Ca2+ transient is larger in dorsal root ganglion (DRG) neurons from tumor-bearing mice compared with that of neurons from naive mice, and the change is mimicked by coculturing DRG neurons with the fibrosarcoma cells used to generate the tumors (Khasabova et al., 2007). The effect of palmitoylethanolamide (PEA), a ligand for the peroxisome proliferator-activated receptor α (PPARα), was determined on the evoked-Ca2+ transient in the coculture condition. The level of PEA was reduced in DRG cells from tumor-bearing mice as well as those cocultured with fibrosarcoma cells. Pretreatment with PEA, a synthetic PPARα agonist (GW7647), or ARN077, an inhibitor of the enzyme that hydrolyzes PEA, acutely decreased the amplitude of the evoked Ca2+ transient in small DRG neurons cocultured with fibrosarcoma cells. The PPARα antagonist GW6471 blocked the effect of each. In contrast, the PPARα agonist was without effect in the control condition, but the antagonist increased the amplitude of the Ca2+ transient, suggesting that PPARα receptors are saturated by endogenous ligand under basal conditions. Effects of drugs on mechanical sensitivity in vivo paralleled their effects on DRG neurons in vitro. Local injection of ARN077 decreased mechanical hyperalgesia in tumor-bearing mice, and the effect was blocked by GW6471. These data support the conclusion that the activity of DRG neurons is rapidly modulated by PEA through a PPARα-dependent mechanism. Moreover, agents that increase the activity of PPARα may provide a therapeutic strategy to reduce tumor-evoked pain.
与来自未处理小鼠的神经元相比，荷瘤小鼠的背根神经节 (DRG) 神经元中去极化诱发的 Ca2+ 瞬变幅度更大，并且这种变化可通过将 DRG 神经元与用于产生肿瘤的纤维肉瘤细胞共培养来模拟 (Khasabova 等人，2007 年)。测定了过氧化物酶体增殖物激活受体 α (PPARα) 配体棕榈酸乙醇酰胺 (PEA) 对共培养条件下诱发的 Ca2+ 瞬变的影响。荷瘤小鼠以及与纤维肉瘤细胞共培养的 DRG 细胞中的 PEA 水平降低。PEA 的预处理，一种合成的 PPARα 激动剂 (GW7647) 或抑制 PEA 水解的酶的抑制剂 ARN077，急性降低了与纤维肉瘤细胞共培养的小 DRG 神经元中诱发的 Ca2+ 瞬变的幅度。PPARα 拮抗剂 GW6471 阻断了每种药物的作用。相反，PPARα 激动剂在对照条件下没有作用，但拮抗剂增加了 Ca2+ 瞬变的幅度，这表明在基础条件下，PPARα 受体被内源性配体饱和。药物对体内机械敏感性的影响与它们在体外对 DRG 神经元的影响相平行。ARN077 的局部注射降低了荷瘤小鼠的机械性痛觉过敏，而 GW6471 阻断了该作用。这些数据支持以下结论：通过 PPARα 依赖性机制，PEA 可快速调节 DRG 神经元的活性。此外，增加 PPARα 活性的药物可能为减少肿瘤诱发的疼痛提供一种治疗策略。
