Ray Kristeena, Fahrmann Johannes, Mitchell Brenda, Paul Dennis, King Holly, Crain Courtney, Cook Carla, Golovko Mikhail, Brose Stephen, Golovko Svetlana, Santanam Nalini
Departments of Pharmacology, Physiology, and Toxicology Biochemistry and Microbiology, and Obstetrics and Gynecology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, USA Department of Basic Sciences, University of North Dakota, Grand Forks, ND, USA.
Pain. 2015 Mar;156(3):528-539. doi: 10.1097/01.j.pain.0000460321.72396.88.
Endometriosis is a disease characterized by the growth of endometrial tissue outside the uterus and is associated with chronic pelvic pain. Peritoneal fluid (PF) of women with endometriosis is a dynamic milieu and is rich in inflammatory markers, pain-inducing prostaglandins prostaglandin E2 and prostaglandin F2α, and lipid peroxides; and the endometriotic tissue is innervated with nociceptors. Our clinical study showed that the abundance of oxidatively modified lipoproteins in the PF of women with endometriosis and the ability of antioxidant supplementation to alleviate endometriosis-associated pain. We hypothesized that oxidatively modified lipoproteins present in the PF are the major source of nociceptive molecules that play a key role in endometriosis-associated pain. In this study, PF obtained from women with endometriosis or control women were used for (1) the detection of lipoprotein-derived oxidation-sensitive pain molecules, (2) the ability of such molecules to induce nociception, and (3) the ability of antioxidants to suppress this nociception. LC-MS/MS showed the generation of eicosanoids by oxidized-lipoproteins to be similar to that seen in the PF. Oxidatively modified lipoproteins induced hypothermia (intracerebroventricular) in CD-1 mice and nociception in the Hargreaves paw withdrawal latency assay in Sprague-Dawley rats. Antioxidants, vitamin E and N-acetylcysteine, and the nonsteroidal anti-inflammatory drug indomethacin suppressed the pain-inducing ability of oxidatively modified lipoproteins. Treatment of human endometrial cells with oxidatively modified lipoproteins or PF from women with endometriosis showed upregulation of similar genes belonging to opioid and inflammatory pathways. Our finding that oxidatively modified lipoproteins can induce nociception has a broader impact not only on the treatment of endometriosis-associated pain but also on other diseases associated with chronic pain.
子宫内膜异位症是一种以子宫外子宫内膜组织生长为特征的疾病，与慢性盆腔疼痛相关。患有子宫内膜异位症的女性的腹腔液（PF）是一个动态环境，富含炎症标志物、诱导疼痛的前列腺素前列腺素E2和前列腺素F2α以及脂质过氧化物；并且子宫内膜异位组织由伤害感受器支配。我们的临床研究表明，子宫内膜异位症女性的PF中氧化修饰脂蛋白的丰度以及抗氧化剂补充剂缓解子宫内膜异位症相关疼痛的能力。我们假设PF中存在的氧化修饰脂蛋白是在子宫内膜异位症相关疼痛中起关键作用的伤害性分子的主要来源。在本研究中，从患有子宫内膜异位症的女性或对照女性获得的PF用于（1）检测脂蛋白衍生的氧化敏感疼痛分子，（2）此类分子诱导伤害感受的能力，以及（3）抗氧化剂抑制这种伤害感受的能力。液相色谱-串联质谱（LC-MS/MS）显示氧化脂蛋白产生类花生酸的情况与PF中所见相似。氧化修饰脂蛋白在CD-1小鼠中诱导体温过低（脑室内），并在Sprague-Dawley大鼠的哈格里夫斯足撤离潜伏期试验中诱导伤害感受。抗氧化剂维生素E和N-乙酰半胱氨酸以及非甾体抗炎药吲哚美辛抑制了氧化修饰脂蛋白的疼痛诱导能力。用氧化修饰脂蛋白或患有子宫内膜异位症女性的PF处理人子宫内膜细胞显示属于阿片样物质和炎症途径的相似基因上调。我们发现氧化修饰脂蛋白可诱导伤害感受，这不仅对子宫内膜异位症相关疼痛的治疗有更广泛的影响，而且对其他与慢性疼痛相关的疾病也有影响。
