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

Gregus, Ann M.a,b,*; Buczynski, Matthew W.b,c; Dumlao, Darren S.c,d; Norris, Paul C.c,d; Rai, Ganeshae; Simeonov, Antone; Maloney, David J.e; Jadhav, Ajite; Xu, Qinghaoa; Wei, Spencer C.d; Fitzsimmons, Bethany L.a; Dennis, Edward A.c,d; Yaksh, Tony L.a,d

doi: 10.1097/j.pain.0000000000001373
Research Paper

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.

Microglial 12/15-lipoxygenases contribute to spinal TLR4-dependent allodynia in male rats that is unresponsive to nonsteroidal anti-inflammatory drugs but is significantly attenuated by inhibitors or antibodies targeting 15-LOX-1.

aDepartment of Anesthesiology, University of California, San Diego, La Jolla, CA, United States

bSchool of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA, United States

cDepartment of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, United States

dDepartment of Pharmacology, University of California, San Diego, La Jolla, CA, United States

eNational Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, MD, United States

Corresponding author. Address: School of Neuroscience, Virginia Polytechnic and State University, 970 Washington Street SW, Life Sciences 1 Room 122 (MC-0910), Blacksburg, VA 24061, United States. Tel.: (540) 231-4089; fax: (540) 231-1475. E-mail: agregus@vt.edu (A.M. Gregus).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received February 25, 2018

Accepted August 06, 2018

© 2018 International Association for the Study of Pain
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