Bulleyaconitine A (BAA), a C19-diterpenoid
alkaloid, has been prescribed as a nonnarcotic
analgesic to treat
chronic pain over four decades in China. The present study investigated its inhibition in
morphine-induced
withdrawal symptoms, conditioned place preference (
CPP) and locomotor sensitization, and then explored the underlying mechanisms of actions. Multiple daily
injections of
morphine but not BAA up to 300 μg/kg/day into mice evoked
naloxone-induced
withdrawal symptoms (i.e., shakes, jumps, genital licks, fecal excretion and
body weight loss),
CPP expression, and locomotor sensitization. Single subcutaneous BAA injection (30-300 μg/kg) dose-dependently and completely attenuated
morphine-induced
withdrawal symptoms, with ED50 values of 74.4 and 105.8 μg/kg in shakes and
body weight loss, respectively. Subcutaneous BAA (300 μg/kg) also totally alleviated
morphine-induced
CPP acquisition and expression and locomotor sensitization. Furthermore, subcutaneous BAA injection also specifically stimulated
dynorphin A expression in microglia but not astrocytes or neurons in nucleus accumbens (NAc) and hippocampal, measured for gene and
protein expression and double immunofluorescence staining. In addition, subcutaneous BAA-inhibited
morphine-induced
withdrawal symptoms and
CPP expression were totally blocked by the microglial metabolic inhibitor
minocycline,
dynorphin A antiserum, or specific KOR antagonist GNTI, given intracerebroventricularly. These results, for the first time, illustrate that BAA attenuates
morphine-induced
withdrawal symptoms,
CPP expression, and locomotor sensitization by stimulation of microglial
dynorphin A expression in the brain, suggesting that BAA may be a potential candidate for treatment of
opioids-induced physical dependence and addiction.