Analgesic Effect of Toll-like Receptor 4 Antagonistic Peptide 2 on Mechanical Allodynia Induced with Spinal Nerve Ligation in Rats
- Author:
Yuhua YIN
1
;
Hyewon PARK
;
Sun Yeul LEE
;
Won Hyung LEE
;
Hee Jung SONG
;
Jinhyun KIM
;
Dong Woon KIM
;
Jinpyo HONG
Author Information
- Publication Type:Original Article
- Keywords: Neuropathic pain; Toll-like receptor 4; Analgesics; Microglia
- MeSH: Analgesics; Animals; Down-Regulation; Gene Expression; Hyperalgesia; Interleukin-6; Interleukins; Ligation; Microglia; Neuralgia; Nitric Oxide Synthase Type II; Polymerase Chain Reaction; Prostaglandin-Endoperoxide Synthases; Rats; Reactive Oxygen Species; RNA, Messenger; Spinal Cord Dorsal Horn; Spinal Nerves; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha
- From:Experimental Neurobiology 2019;28(3):352-361
- CountryRepublic of Korea
- Language:English
- Abstract: Neuroinflammation is one of the key mechanisms of neuropathic pain, which is primarily mediated by the Toll-like receptor 4 (TLR4) signaling pathways in microglia. Therefore, TLR4 may be a reasonable target for treatment of neuropathic pain. Here, we examined the analgesic effect of TLR4 antagonistic peptide 2 (TAP2) on neuropathic pain induced by spinal nerve ligation in rats. When lipopolysaccharide (LPS)-stimulated BV2 microglia cells were treated with TAP2 (10 µM), the mRNA levels of proinflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS), were markedly decreased by 54–83% as determined by quantitative PCR (qPCR) analysis. Furthermore, when TAP2 (25 nmol in 20 µL PBS) was intrathecally administered to the spinal nerve ligation-induced rats on day 3 after surgery, the mechanical allodynia was markedly decreased for approximately 2 weeks in von Frey filament tests, with a reduction in microglial activation. On immunohistochemical and qPCR analyses, both the level of reactive oxygen species and the gene expression of the proinflammatory mediators, such as TNF-α, IL-1β, IL-6, COX-2, and iNOS, were significantly decreased in the ipsilateral spinal dorsal horn. Finally, the analgesic effect of TAP2 was reproduced in rats with monoiodoacetate-induced osteoarthritic pain. The findings of the present study suggest that TAP2 efficiently mitigates neuropathic pain behavior by suppressing microglial activation, followed by downregulation of neuropathic pain-related factors, such as reactive oxygen species and proinflammatory molecules. Therefore, it may be useful as a new analgesic for treatment of neuropathic pain.
