Inhibition of spinal 15-LOX-1 attenuates TLR4-dependent, nonsteroidal anti-inflammatory drug–unresponsive hyperalgesia in male rats Article Swipe
Ann M. Gregus
,
Matthew W. Buczynski
,
Darren S. Dumlao
,
Paul C. Norris
,
Ganesha Rai
,
Anton Simeonov
,
David J. Maloney
,
Ajit Jadhav
,
Qinghao Xu
,
Spencer C. Wei
,
Bethany Fitzsimmons
,
Edward A. Dennis
,
Tony L. Yaksh
·
YOU?
·
· 2018
· Open Access
·
· DOI: https://doi.org/10.1097/j.pain.0000000000001373
YOU?
·
· 2018
· Open Access
·
· DOI: https://doi.org/10.1097/j.pain.0000000000001373
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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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1097/j.pain.0000000000001373
- OA Status
- gold
- Cited By
- 18
- References
- 85
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2890346134
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W2890346134Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1097/j.pain.0000000000001373Digital Object Identifier
- Title
-
Inhibition of spinal 15-LOX-1 attenuates TLR4-dependent, nonsteroidal anti-inflammatory drug–unresponsive hyperalgesia in male ratsWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2018Year of publication
- Publication date
-
2018-08-16Full publication date if available
- Authors
-
Ann M. Gregus, Matthew W. Buczynski, Darren S. Dumlao, Paul C. Norris, Ganesha Rai, Anton Simeonov, David J. Maloney, Ajit Jadhav, Qinghao Xu, Spencer C. Wei, Bethany Fitzsimmons, Edward A. Dennis, Tony L. YakshList of authors in order
- Landing page
-
https://doi.org/10.1097/j.pain.0000000000001373Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://escholarship.org/uc/item/338344zjDirect OA link when available
- Concepts
-
TLR4, Pharmacology, Spinal cord, Cyclooxygenase, Allodynia, Microglia, Hyperalgesia, Nociception, Chemistry, Medicine, Neuropathic pain, Anesthesia, Inflammation, Receptor, Immunology, Biochemistry, Enzyme, PsychiatryTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
18Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 3, 2024: 5, 2023: 3, 2021: 3, 2020: 2Per-year citation counts (last 5 years)
- References (count)
-
85Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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