Inducible Lentivirus-Mediated siRNA against TLR4 Reduces Nociception in a Rat Model of Bone Cancer Pain

Ruirui Pan,Jinming Zhang,Feixiang Wu,Zhangxiang Huang,Huiting Di,Yuming Sun,Weifeng Yu

doi:10.1155/2015/523896

Abstract

Although bone cancer pain is still not fully understood by scientists and clinicians alike, studies suggest that toll like receptor 4 (TLR4) plays an important role in the initiation and/or maintenance of pathological pain state in bone cancer pain. A promising treatment for bone cancer pain is the downregulation of TLR4 by RNA interference; however, naked siRNA (small interference RNA) is not effective in long-term treatments. In order to concoct a viable prolonged treatment for bone cancer pain, an inducible lentivirus LvOn-siTLR4 (tetracycline inducible lentivirus carrying siRNA targeting TLR4) was prepared and the antinociception effects were observed in bone cancer pain rats induced by Walker 256 cells injection in left leg. Results showed that LvOn-siTLR4 intrathecal injection with doxycycline (Dox) oral administration effectively reduced the nociception induced by Walker 256 cells while inhibiting the mRNA and protein expression of TLR4. Proinflammatory cytokines as TNF-α and IL-1β in spinal cord were also decreased. These findings suggest that TLR4 could be a target for bone cancer pain treatment and tetracycline inducible lentivirus LvOn-siTLR4 represents a new potential option for long-term treatment of bone cancer pain.

Highlights

Cancer-induced bone pain, characterized by spontaneous pain, hyperalgesia, and allodynia, is estimated to affect about 36%–50% of cancer patients [1]
In contrast to the Lv-MM group and normal saline (NS) group, mechanical allodynia was decreased in the LvOn-siTLR4 with DOX group on the 3rd, 7th, 14th, and 21st days after viral injection (P < 0.01), which suggested that the small RNA expressed by the lentivirus was effective
In the LvOn-siTLR4 group, rats without Dox had no effect in mechanical allodynia, which illustrated that the expression of small RNA was induced by Dox

Summary

Introduction

Cancer-induced bone pain, characterized by spontaneous pain, hyperalgesia, and allodynia, is estimated to affect about 36%–50% of cancer patients [1]. Bone cancer pain is considered to be mechanistically unique compared with inflammatory or neuropathic pain states [3]. The activation and upregulation of glial cells in the spinal cord play an important role in initiation and/or maintenance of pathological pain state in bone cancer pain [4, 5]. One of the neuron-to-glial activation signals has proposed that proinflammatory cytokines, such as IL-1, IL-6, and TNFα, were released via the microglial TLR4 receptor in a rat model of bone cancer pain [6]. Blocking the TLR4 signaling pathway might be a useful way of treating bone cancer pain

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Conclusion