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Original Article

Exp Neurobiol 2019; 28(3): 352-361

Published online June 26, 2019

© The Korean Society for Brain and Neural Sciences

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

Yuhua Yin1,2, Hyewon Park1,2, Sun Yeul Lee3, Won-hyung Lee3, Hee-Jung Song4, Jinhyun Kim3, Dong Woon Kim1,2*, and Jinpyo Hong2*

1Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea.

2Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 35015, Korea.

3Department of Anesthesia and Pain Medicine, Chungnam National University Hospital, Daejeon 35015, Korea.

4Department of Neurology, Chungnam National University Hospital, Daejeon 35015, Korea.

5Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Korea.

Correspondence to: *To whom correspondence should be addressed.
Jinpyo Hong, TEL: 82-42-580-8209, FAX: 82-42-580-4800, e-mail:
Dong Woon Kim, TEL: 82-42-580-8207, FAX: 82-42-580-4800, e-mail:
Jinpyo Hong author's current address: Department of Neuroscience and Physiology, and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 08826, Korea. Tel: +82-2-880-2314, Fax: +82-2-880-2314, e-mail:

Received: January 31, 2019; Revised: May 11, 2019; Accepted: May 28, 2019

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.

Graphical Abstract

Keywords: Neuropathic pain, Toll-like receptor 4, Analgesics, Microglia