Peroxisome proliferator-activated receptor α mediates acute effects of palmitoylethanolamide on sensory neurons.
Peroxisome proliferator-activated receptor α mediates acute effects of palmitoylethanolamide on sensory neurons.
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DOI：
10.1523/jneurosci.0130-12.2012
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发表时间：
2012-09-12
期刊：
影响因子：
--
通讯作者：
Seybold V
中科院分区：
文献类型：
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作者：
Khasabova IA;Xiong Y;Coicou LG;Piomelli D;Seybold V
去极化诱发的Ca2+瞬变的幅度是更大的背根神经节（DRG）神经元从荷瘤小鼠相比，从幼稚小鼠的神经元，和变化是模仿共培养DRG神经元与用于产生肿瘤的纤维肉瘤细胞。在共培养条件下，测定了过氧化物酶体增殖物激活受体α（PPARα）的配体棕榈酰乙醇胺（PEA）对诱发的钙瞬变的影响。PEA水平在荷瘤小鼠DRG细胞以及与纤维肉瘤细胞共培养的DRG细胞中降低。在与纤维肉瘤细胞共培养的小DRG神经元中，用合成的PPARα激动剂（GW7647）PEA或水解PEA的酶的抑制剂ARN077预处理可急剧降低诱发的Ca 2+瞬变的幅度。PPARα拮抗剂GW6471可阻断这两种作用。相比之下，在对照条件下，PPARα激动剂没有作用，但拮抗剂增加了Ca2+瞬变的幅度，表明在基础条件下，PPARα受体被内源性配体饱和。药物在体内对机械敏感性的影响与其在体外对DRG神经元的影响相同。局部注射ARN077可降低荷瘤小鼠的机械性痛觉过敏，该作用可被GW 6471阻断。这些数据支持PEA通过PPARα依赖性机制快速调节DRG神经元活动的结论。此外，增加PPARα活性的药物可能提供减少肿瘤诱发疼痛的治疗策略。
The amplitude of the depolarization-evoked Ca2+ transient is larger in dorsal root ganglion (DRG) neurons from tumor-bearing mice compared to that of neurons from naive mice, and the change is mimicked by co-culturing DRG neurons with the fibrosarcoma cells used to generate the tumors. The effect of palmitoylethanolamide (PEA), a ligand for the peroxisome proliferator-activated receptor-alpha (PPARα), was determined on the evoked-Ca2+ transient in the co-culture condition. The level of PEA was reduced in DRG cells from tumor-bearing mice as well as those co-cultured with fibrosarcoma cells. Pretreatment with PEA, a synthetic PPARα agonist (GW7647), or ARN077, an inhibitor of the enzyme that hydrolyses PEA, acutely decreased the amplitude of the evoked Ca2+ transient in small DRG neurons co-cultured 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.