1. 2016;19;465-476Tanshinone IIA Exerts an Antinociceptive Effect in Rats with Cancer-induced Bone Pain
   Randomized Trial
   Alan D. Kaye, MD, PhD, Jian-xiang Niu, PhD, Fan Yang, PhD, Lei Chen, MD, PhD, Li-fang Wu, MD, Wei Hao, PhD, and Shi-yuan Xu, PhD.

BACKGROUND: Cancer-induced bone pain (CIBP) is a common chronic pain characterized by 2 components, ongoing pain and breakthrough pain. Tanshinone IIA (TSN IIA) is a bioactive constituent of the traditional Chinese medicine Danshen, which has been reported to have an antinociceptive effect on neuropathic and inflammatory pain through downregulation of the late proinflammatory cytokine high-mobility group protein B1 (HMGB1).

OBJECTIVE: To assess the antinociceptive effect of TSN IIA on CIBP.

STUDY DESIGN: A randomized, double-blind, controlled animal trial was performed.

SETTING: University lab in China.

METHODS: A rat CIBP model was established by injecting Walker 256 mammary gland carcinoma cells into the intramedullary cavity of the tibia. Both ongoing pain, e.g., flinching and guarding, and breakthrough pain, e.g., limb use and von Frey threshold, were evaluated. The effects of intraperitoneally administered TSN IIA on pain behavior and the expression levels of spinal HMGB1, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6 were determined. The effect of TSN IIA on the electrically evoked response of spinal wide-dynamic range (WDR) neurons was performed in vivo.

RESULTS: TSN IIA dose-dependently inhibited cancer-induced ongoing pain and breakthrough pain. The expression levels of spinal HMGB1 and other inflammatory factors (IL-1beta, TNF-alpha, and IL-6) were increased in the rat model, but they were suppressed by TSN IIA in a dose-dependent manner. Moreover, TSN IIA significantly inhibited the neuronal responses of WDR neurons in spinal deep layers.

LIMITATIONS: Further studies are warranted to ascertain how TSN IIA attenuates cancer-induced ongoing pain.

CONCLUSIONS: Our results indicate that TSN IIA attenuates cancer-induced ongoing pain and breakthrough pain, possibly via suppression of central sensitization in CIBP rats. Therefore, we have provided strong evidence supporting TSN IIA as a potential and effective therapy for relieving CIBP.

Key words: Cancer-induced bone pain, high-mobility group protein B1, Tanshinone IIA, ongoing pain, breakthrough pain