Abstract
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.
Highlights
Opioid addiction is the accumulated results of tolerance and dependence, mainly including physical and psychological dependence (Wang et al, 2019)
Withdrawal symptoms were developed after bi-daily subcutaneous morphine injections into mice for 7 consecutive days, which was reflected by withdrawal signs following application of naloxone
Bi-daily subcutaneous Bulleyaconitine A (BAA) injections with a dose up to 300 μg/kg/day for 7 days did not induce any withdrawal symptoms, which is consistent with the previous finding in which daily subcutaneous BAA did not induce jumping responses following nalorphine challenge (Tang et al, 1986)
Summary
Opioid addiction is the accumulated results of tolerance and dependence, mainly including physical and psychological dependence (Wang et al, 2019). Psychological dependence refers to drug craving and euphoria achieved by repeated medication, which is difficult to eliminate. Morphine and related opioids are the most potent and widely used analgesics in treating moderate to severe pain. Development of tolerance and dependence are the important limitation to use of opioid drugs in chronic pain management (Thorn et al, 2016; Ruzza et al, 2019). Opioid addiction in Western countries, in the United States, has become a serious health and social problem in recent years, which requires to be urgently addressed (Wingo et al, 2016; Ezard et al, 2018)
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