title: Oxidation-sensitive nociception involved in endometriosis-associated pain.
abstract: 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.
authors.affiliation: 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.
authors.forename: Kristeena
authors.initials: K
authors.lastname: Ray
authors.forename: Johannes
authors.initials: J
authors.lastname: Fahrmann
authors.forename: Brenda
authors.initials: B
authors.lastname: Mitchell
authors.forename: Dennis
authors.initials: D
authors.lastname: Paul
authors.forename: Holly
authors.initials: H
authors.lastname: King
authors.forename: Courtney
authors.initials: C
authors.lastname: Crain
authors.forename: Carla
authors.initials: C
authors.lastname: Cook
authors.forename: Mikhail
authors.initials: M
authors.lastname: Golovko
authors.forename: Stephen
authors.initials: S
authors.lastname: Brose
authors.forename: Svetlana
authors.initials: S
authors.lastname: Golovko
authors.forename: Nalini
authors.initials: N
authors.lastname: Santanam
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001202:Ascitic Fluid / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004715:Endometriosis / Q000150:complications*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008084:Lipoxygenase; D051379:Mice; D008875:Middle Aged; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement; D017699:Pelvic Pain / Q000209:etiology* / Q000378:metabolism*; D010545:Peroxides / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors; D014810:Vitamin E / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D008077:Lipoproteins, LDL; D010545:Peroxides; D017392:Thiobarbituric Acid Reactive Substances; D014810:Vitamin E; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin