Bulleyaconitine A Exerts Antianxiety and Antivisceral Hypersensitivity Effects

Abstract

Visceral pain is one of the leading causes for abdominal pain in gastroenterological diseases and is still hard to treat effectively. Bulleyaconitine A (BAA) is an aconitine analog and has been used for the treatment of pain. Our previous work suggested that BAA exerted analgesic effects on neuropathic pain through stimulating the expression of dynorphin A in spinal microglia. Here, we investigated the inhibitory effect of BAA on visceral pain and examined whether the expression of dynorphin A in spinal microglia was responsible for its effects. We found that BAA produced significant antivisceral pain effect induced by acetic acid through stimulating dynorphin A expression in spinal microglia. In addition, anxiety and chronic visceral pain are highly prevalent comorbid conditions in clinical research, which is still a problem to be solved. We also aimed to evaluate the effects of BAA on anxiety. A comorbidity model with characteristics of both chronic visceral pain and anxiety was developed by colorectal injection of 2,4,6-trinitrobenzene sulfonic acid and the induction of heterotypic intermittent chronic stress protocol. In comorbid animals, BAA exerted great antianxiety effects. Meanwhile, the antianxiety mechanism of BAA was different with the antivisceral pain mechanism of BAA. In conclusion, our study demonstrated, for the first time, that BAA exerted marked antivisceral pain and antianxiety effects, which expands the analgesic spectrum and clinical application of BAA. Furthermore, it also it provides a better guidance for the clinical use of BAA.

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

“…The results are in agreement with the previous publications that the κ-opioid receptor agonist salvinorin A punished self-administration of cocaine and remifentanil in monkeys (Freeman et al, 2014), and that addition of the κ-opioid receptor agonist U69,593 to fentanyl produced a proportion-dependent decrease of fentanyl self-administration in rats (Negus et al, 2008). In agreement, GNTI and other specific κ-opioid receptor antagonist nor-BNI (but not the μ-or δ-opioid receptor antagonist) blocked the antinociceptive effects of BAA (Li et al, 2016b;Huang et al, 2020b), bullatine A (Huang et al, 2016) and lappaconitine (Sun et al, 2018) in the rodent models of neuropathic pain, bone cancer pain, inflammatory pain and visceral pain.…”

“…As it is a nonnarcotic analgesic and has lower toxicity and wider treatment window than aconitine, BAA has been widely prescribed in China to treat various forms of chronic pain over four decades (Bello-Ramirez and Nava-Ocampo, 2004;Xie et al, 2018). Accumulated evidence demonstrated that BAA and its analogs aconitine (C19-diterpenoid), bullatine A (C20-diterpenoid) and lappaconitine (C18-diterpenoid) produced antinociception without induction of antinociceptive tolerance in various rodent models of pain hypersensitivity, including neuropathic pain, bone cancer pain, inflammatory pain, diabetic pain, and visceral pain (Li et al, 2016a;Li et al, 2016b;Huang et al, 2017a;Huang et al, 2020a;Huang et al, 2020b). Our recent studies further uncovered that BAA, aconitines, bullatine A and lappaconitine alleviated pain directly through stimulating spinal microglial dynorphin A expression and subsequent activating κ-opioid receptors in a variety of rodent models of pain hypersensitivity (Huang et al, 2017a;Li et al, 2017;Sun et al, 2018).…”

Effects of alkaloids on peripheral neuropathic pain: a review

“…The results support that the antinociceptive effects of lappaconitine are entirely blocked by intrathecal injection of the specific dynorphin A antibody and κ-opioid receptor antagonist [29]. Interestingly, it seems that the alkaloids bioactive components from the medicinal plants of Ranunculus can induce the production of dynorphin A in the spinal cord [25,135,139]. Huang et al explored the analgesic mechanism of BA by studying the release of inflammatory factors and microglia dynorphin A.…”

Bulleyaconitine A Inhibits Visceral Nociception and Spinal Synaptic Plasticity through Stimulation of Microglial Release of Dynorphin A

“…Rats were given 30 minutes to accommodate the environment after they woke up. The balloon was then distended at four different pressures (20,40,60, and 80 mmHg) of graded colorectal distension. The distention at each pressure was maintained for 20 seconds at an interval of 5 minutes and repeated for three times.…”

“…In addition, it was proposed that activation of the descending inhibitory transmission by norepinephrine and serotonin was associated with the antinociceptive effects of BAA and its analogs mesaconitine, 3-acetylaconitine, and lappaconitine [9,16,17]. In contrast, our laboratory recently demonstrated that BAA and its analogs aconitine, bullatine, and lappaconitine, given subcutaneously or intrathecally, blocked the spinal nerve ligation-induced neuropathic pain by the stimulation of the spinal microglial expression of dynorphin A [10,[18][19][20].…”