Bulleyaconitine A inhibits morphine physical and psychological dependence via dynorphin A expression

Abstract

Background and purpose: Drug addiction is a chronic and recurrent brain disease, which has become a social problem in recent years. Our study investigated Bulleyaconitine A (BAA) inhibition in physical and psychological dependence and explored underlying mechanisms of action. Experiment approach: Naloxone-induces withdrawal signs in morphine mice and conditioned place preference (CPP) paradigm were used. Prodynorphin gene expression and dynorphin A level were measured in nucleus accumbens (NAc) and hippocampal CA1. Double immunofluorescence staining of dynorphin A with glia and neuronal cellular biomarkers was detected in NAc and hippocampal CA1. Key results: 1 Multiple daily injections of morphine in mice induced withdrawal signs and conditioned place preference (CPP) acquisition. 2 Single subcutaneous injection of BAA (30-300 μg/kg) dose-dependently and attenuated morphine withdrawal signs, and BAA (300 μg/kg) also totally alleviated morphine CPP acquisition. 3 BAA specifically stimulated the expression of dynorphin A in microglia in NAc and hippocampal CA1, measured by gene and protein expression and double immunofluorescence staining. 4 BAA-inhibited naloxone-induced withdrawal signs and CPP acquisition were totally blocked by the microglial activation inhibitor minocycline, dynorphin A antiserum and specific κ-opioid receptor antagonist GNTI. Conclusions & implications: Our results, for the first time, illustrate that BAA attenuates morphine-induced physical and psychological dependence by stimulation of microglial dynorphin A expression in brain and suggest that BBA may be a potential candidate for the treatment of opioid drug addiction.