دورية أكاديمية
أعرض في EDS

Inhibition of spinal 15-LOX-1 attenuates TLR4-dependent, nonsteroidal anti-inflammatory drug-unresponsive hyperalgesia in male rats.

التفاصيل البيبلوغرافية
العنوان: Inhibition of spinal 15-LOX-1 attenuates TLR4-dependent, nonsteroidal anti-inflammatory drug-unresponsive hyperalgesia in male rats.
المؤلفون: Gregus AM; Department of Anesthesiology, University of California, San Diego, La Jolla, CA, United States.; School of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA, United States., Buczynski MW; School of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA, United States.; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, United States., Dumlao DS; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, United States.; Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States., Norris PC; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, United States.; Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States., Rai G; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United States., Simeonov A; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United States., Maloney DJ; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United States., Jadhav A; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United States., Xu Q; Department of Anesthesiology, University of California, San Diego, La Jolla, CA, United States., Wei SC; Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States., Fitzsimmons BL; Department of Anesthesiology, University of California, San Diego, La Jolla, CA, United States., Dennis EA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, United States.; Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States., Yaksh TL; Department of Anesthesiology, University of California, San Diego, La Jolla, CA, United States.; Department of Pharmacology, University of California, San Diego, La Jolla, CA, United States.
المصدر: Pain [Pain] 2018 Dec; Vol. 159 (12), pp. 2620-2629.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 7508686 Publication Model: Print Cited Medium: Internet ISSN: 1872-6623 (Electronic) Linking ISSN: 03043959 NLM ISO Abbreviation: Pain Subsets: MEDLINE
أسماء مطبوعة: Publication: 2015- : Hagerstown, MD : Lippincott Williams & Wilkins
Original Publication: Amsterdam, Elsevier/North-Holland.
مواضيع طبية MeSH: Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use , Hyperalgesia/*drug therapy , Hyperalgesia/*metabolism , Lipoxygenases/*therapeutic use , Neuroglia/*drug effects , Toll-Like Receptor 4/*metabolism, 8,11,14-Eicosatrienoic Acid/analogs & derivatives ; 8,11,14-Eicosatrienoic Acid/metabolism ; Animals ; Animals, Newborn ; Cells, Cultured ; Chromatography, Liquid ; Enzyme Inhibitors/therapeutic use ; Lipopolysaccharides/toxicity ; Male ; Mass Spectrometry ; Physical Stimulation/adverse effects ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/cytology ; Toll-Like Receptor 4/antagonists & inhibitors ; Transfection
مستخلص: Although nonsteroidal anti-inflammatory drugs are the first line of therapeutics for the treatment of mild to moderate somatic pain, they are not generally considered to be effective for neuropathic pain. In the current study, direct activation of spinal Toll-like 4 receptors (TLR4) by the intrathecal (IT) administration of KDO2 lipid A (KLA), the active component of lipopolysaccharide, elicits a robust tactile allodynia that is unresponsive to cyclooxygenase inhibition, despite elevated expression of cyclooxygenase metabolites in the spinal cord. Intrathecal KLA increases 12-lipoxygenase-mediated hepoxilin production in the lumbar spinal cord, concurrent with expression of the tactile allodynia. The TLR4-induced hepoxilin production was also observed in primary spinal microglia, but not in astrocytes, and was accompanied by increased microglial expression of the 12/15-lipoxygenase enzyme 15-LOX-1. Intrathecal KLA-induced tactile allodynia was completely prevented by spinal pretreatment with the 12/15-lipoxygenase inhibitor CDC or a selective antibody targeting rat 15-LOX-1. Similarly, pretreatment with the selective inhibitors ML127 or ML351 both reduced activity of the rat homolog of 15-LOX-1 heterologously expressed in HEK-293T cells and completely abrogated nonsteroidal anti-inflammatory drug-unresponsive allodynia in vivo after IT KLA. Finally, spinal 12/15-lipoxygenase inhibition by nordihydroguaiaretic acid (NDGA) both prevents phase II formalin flinching and reverses formalin-induced persistent tactile allodynia. Taken together, these findings suggest that spinal TLR4-mediated hyperpathic states are mediated at least in part through activation of microglial 15-LOX-1.
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معلومات مُعتمدة: R01 DA002110 United States DA NIDA NIH HHS; U54 GM069338 United States GM NIGMS NIH HHS; R01 GM020501 United States GM NIGMS NIH HHS; K99 DA035865 United States DA NIDA NIH HHS; F32 GM020501 United States GM NIGMS NIH HHS; R01 GM064611 United States GM NIGMS NIH HHS; R01 NS099338 United States NS NINDS NIH HHS; R00 DA035865 United States DA NIDA NIH HHS
المشرفين على المادة: 0 (Anti-Inflammatory Agents, Non-Steroidal)
0 (Enzyme Inhibitors)
0 (Lipopolysaccharides)
0 (RNA, Messenger)
0 (Toll-Like Receptor 4)
85589-24-8 (8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid)
EC 1.13.11.- (Lipoxygenases)
FC398RK06S (8,11,14-Eicosatrienoic Acid)
تواريخ الأحداث: Date Created: 20180822 Date Completed: 20190219 Latest Revision: 20221005
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6237621
DOI: 10.1097/j.pain.0000000000001373
PMID: 30130298
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-6623
DOI:10.1097/j.pain.0000000000001373