Effects of Salvia miltiorrhiza Bunge extract and its single components on monosodium urate-induced pain in vivo and lipopolysaccharide-induced inflammation in vitro.

OBJECTIVE: To investigate the possible antinociceptive effects of Salvia (S.) miltiorrhiza Bunge and its single components in monosodium urate (MSU)-induced pain model in mice and lipopolysaccharide (LPS)-induced inflammation model in RAW264.7 cells. METHODS: Pretreatment of S. miltiorrhiza Bunge extract (from 1 to 50 µg/mL) concentration-dependently attenuated LPS-induced nitric oxide (NO) release. The extract of S. miltiorrhiza Bunge (50 or 100 mg/kg) also caused reversals of decreased threshold for pain in the MSU-treated group as measured by Von-Frey test. Furthermore, we assessed the antinociceptive and anti-inflammatory properties of the active single components from S. miltiorrhiza Bunge such as 15, 16-dihydrotanshinone Ⅰ tanshinone Ⅱ cryptotanshinone, miltirone, tanshinone ⅡA, and salvianolic acid B. Some of them showed an anti-inflammatory effect in LPS-induced NO release model and an antinociceptive effect in MSU-treated pain model. RESULTS: Our results suggest that S. miltiorrhiza Bunge extract may exert anti-inflammatory effect by reducing LPS-induced NO release and an antinociceptive property in MSU-treated pain model. Especially, tanshinoneⅡA, miltirone, cryptotanshinone, and 15,16-dihydrotanshinone Ⅰ not only appear to be responsible for LPS-induced NO release induced by S. miltiorrhiza Bunge, but also in the production of S. miltiorrhiza Bunge extract-induced antinociception in MSU-treated pain model. CONCLUSION: Therefore, the analgesic and anti-inflammatory property of S. miltiorrhiza Bunge indicate it as a therapeutic potential candidate for the treatment of pain and inflammation.

The Molecular Signatures of Acute-immobilization-induced Antinociception and Chronic-immobilization-induced Antinociceptive Tolerance

In the present study, the productions of antinociception induced by acute and chronic immobilization stress were compared in several animal pain models. In the acute immobilization stress model (up to 1 hr immobilization), the antinociception was produced in writhing, tail-flick, and formalin-induced pain models. In chronic immobilization stress experiment, the mouse was enforced into immobilization for 1 hr/day for 3, 7, or 14 days, then analgesic tests were performed. The antinociceptive effect was gradually reduced after 3, 7 and 14 days of immobilization stress. To delineate the molecular mechanism involved in the antinociceptive tolerance development in the chronic stress model, the expressions of some signal molecules in dorsal root ganglia (DRG), spinal cord, hippocampus, and the hypothalamus were observed in acute and chronic immobilization models. The COX-2 in DRG, p-JNK, p-AMPKα1, and p-mTOR in the spinal cord, p-P38 in the hippocampus, and p-AMPKα1 in the hypothalamus were elevated in acute immobilization stress, but were reduced gradually after 3, 7 and 14 days of immobilization stress. Our results suggest that the chronic immobilization stress causes development of tolerance to the antinociception induced by acute immobilization stress. In addition, the COX-2 in DRG, p-JNK, p-AMPKα1, and p-mTOR in the spinal cord, p-P38 in the hippocampus, and p-AMPKα1 in the hypothalamus may play important roles in the regulation of antinociception induced by acute immobilization stress and the tolerance development induced by chronic immobilization stress.