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J Ethnopharmacol. 2017 Jan 20;196:151-159. doi: 10.1016/j.jep.2016.12.027. Epub 2016 Dec 16.

Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal κ-opioid receptors.

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King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address:



Bullatine A, a C20-diterpenoid alkaloid and one of the major effective ingredients in Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao), can block pain hypersensitivity in a variety of rodent models through expression of spinal microglial dynorphin A.


To assess the interaction between bullatine A and morphine on antinociception in acute nociception and pain hypersensitivity states, with the exogenous synthetic dynorphin A as a comparison MATERIALS AND METHODS: Spinal nerve ligation-induced neuropathic rats and naïve mice were used for assessing the acute and chronic interactions of bullatine A/dynorphin A with morphine.


Single subcutaneous injection of bullatine A or dynorphin A(1-17) did not either alter formalin- and thermally (hot-plate and water immersion tests)-induced acute nociception or potentiate morphine antinociception in naïve mice. In contrast, bullatine A dose-dependently inhibited formalin-induced tonic pain with the efficacy of 54% inhibition and the half-effective dose of 0.9mg/kg. Concurrent bullatine A additively enhanced morphine antinociception. In neuropathic rats, the antinociceptive effects of multiple bidaily intrathecal injections of bullatine A and dynorphin A remained consistent over 13 days, whereas morphine produced progressive and complete tolerance to antinociception, which was completely inhibited by concurrent bullatine A and dynorphin A. A single intrathecal injection of bullatine A and dynorphin A immediately reversed established morphine tolerance in neuropathic rats, although the blockade was a less degree in the thermally induced mouse acute nociceptive tests. The inhibitory effects of bullatine A and dynorphin A on morphine tolerance were immediately and completely attenuated by intrathecal dynorphin A antibody and/or selective κ-opioid receptor antagonist GNTI.


These results suggest that bullatine A produces antinociception without induction of tolerance and inhibits morphine antinociceptive tolerance, and provide pharmacological basis for concurrent bullatine A and morphine treatment for chronic pain and morphine analgesic tolerance.


Bullatine A; Bullatine A (PubChem CID: 102004922); Dynorphin A; Interaction; Morphine; Nociceptive tolerance; dynorphin A(1−17) (PubChem CID: 91928823); morphine (PubChem CID: 5464110)

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