Exp Neurobiol.  2019 Jun;28(3):352-361. 10.5607/en.2019.28.3.352.

Analgesic Effect of Toll-like Receptor 4 Antagonistic Peptide 2 on Mechanical Allodynia Induced with Spinal Nerve Ligation in Rats

• Yin Y
• Park H
• Lee SY
• Lee WH
• Song HJ
• Kim J
• Kim DW
• Hong J

• KMID: 2451071
• DOI: http://doi.org/10.5607/en.2019.28.3.352

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.

Keyword

Neuropathic pain; Toll-like receptor 4; Analgesics; Microglia

MeSH Terms

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
Analgesics
Interleukin-6
Interleukins
Nitric Oxide Synthase Type II
Prostaglandin-Endoperoxide Synthases
RNA, Messenger
Reactive Oxygen Species
Toll-Like Receptor 4
Toll-Like Receptors
Tumor Necrosis Factor-alpha