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. Keywords: BAA, dynorphin A, κ-opioid receptor, nucleus
accumbens (NAc), hippocampal CA1, microglia