Aconitum-Derived Bulleyaconitine A Exhibits Antihypersensitivity Through Direct Stimulating Dynorphin A Expression in Spinal Microglia

Li, Teng-Fei; Fan, Hui; Wang, Yongxiang

doi:10.1016/j.jpain.2015.12.015

Cited by 45 publications

(92 citation statements)

References 79 publications

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“…Importantly, repetitive application of BLA does not induce addiction and tolerance. Recent studies show that oral administration, 30 DRG local application, 31 and intrathecal injection 32 of BLA are effective for inhibition of neuropathic pain, bone cancer-induced pain, and chemotherapy-induced pain in rodents. Importantly, it has been reported that BLA has synergistic effect with morphine and can completely abolish the tolerance of morphine analgesic in rats.…”

Section: The Mechanisms Underlying Analgesic Effect Of Blamentioning

confidence: 99%

“…Importantly, it has been reported that BLA has synergistic effect with morphine and can completely abolish the tolerance of morphine analgesic in rats. 32 …”

Section: The Mechanisms Underlying Analgesic Effect Of Blamentioning

confidence: 99%

“…32 Further studies are needed to evaluate the effects of BLA on glial cells and the gliotransmitters.…”

Section: The Mechanisms Underlying Analgesic Effect Of Blamentioning

confidence: 99%

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Mechanisms for therapeutic effect of bulleyaconitine A on chronic pain

et al. 2018

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Bulleyaconitine A, a diterpenoid alkaloid isolated from Aconitum bulleyanum plants, has been used for the treatment of chronic pain in China since 1985. Clinical studies show that the oral administration of bulleyaconitine A is effective for treating different kinds of chronic pain, including back pain, joint pain, and neuropathic pain with minimal side effect in human patients. The experimental studies have revealed that bulleyaconitine A at therapeutic doses potently inhibits the peripheral sensitization and central sensitization that underlie chronic pain and has no effect on acute pain. Bulleyaconitine A preferably blocks tetrodotoxin-sensitive voltage-gated sodium channels in dorsal root ganglion neurons by inhibition of protein kinase C, and the effect is around 600 times more potent in neuropathic animals than in naïve ones. Bulleyaconitine A at 5 nM inhibits the hypersensitivity of dorsal root ganglion neurons in neuropathic rats but has no effect on excitability of dorsal root ganglion neurons in sham group. Bulleyaconitine A inhibits long-term potentiation at C-fiber synapses in spinal dorsal horn, a synaptic model of pathological pain, preferably in neuropathic pain rats over naïve rats. The following mechanisms may underlie the selective effect of bulleyaconitine A on chronic pain. (1) In neuropathic conditions, protein kinase C and voltage-gated sodium channels in dorsal root ganglion neurons are upregulated, which enhances bulleyaconitine A’s effect. (2) Bulleyaconitine A use-dependently blocks voltage-gated sodium channels and therefore inhibits the ectopic discharges that are important for neuropathic pain. (3) Bulleyaconitine A is shown to inhibit neuropathic pain by the modulation of spinal microglia, which are involved in the chronic pain but not in acute (nociceptive) pain. Moreover, bulleyaconitine A facilitates the anesthetic effect of morphine and inhibits morphine tolerance in rats. Together, bulleyaconitine A is able to inhibit chronic pain by targeting at multiple molecules. Further clinical and experimental studies are needed for evaluating the efficacy of bulleyaconitine A in different forms of chronic pain in patients and for exploring the underlying mechanisms.

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Section: The Mechanisms Underlying Analgesic Effect Of Blamentioning

confidence: 99%

“…Importantly, it has been reported that BLA has synergistic effect with morphine and can completely abolish the tolerance of morphine analgesic in rats. 32 …”

Section: The Mechanisms Underlying Analgesic Effect Of Blamentioning

confidence: 99%

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Mechanisms for therapeutic effect of bulleyaconitine A on chronic pain

et al. 2018

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“…It was initially claimed that the antinociceptive activity of bulleyaconitine A might have some relationship with the voltage-gated sodium channel because it can reduce neuronal Na + current in a use-dependent manner and display long-acting local anesthetic properties in rats. [3] However, according to the result of King's lab recently, [11] bulleyaconitine A actually performs its antinociceptive activity by stimulating the dynorphin A expression in spinal microglia and performs its anti-hypersensitivity [13] in the same way. Dynorphin is known as an analgesic biomaterial produced by the precursor protein prodynorphin expressed in spinal microglia, and it has been proved to have a strong antinociceptive activity.…”

Section: Antinociceptive Activitymentioning

confidence: 99%

“…[23] However, King's group found that the anti-hypersensitivity of bulleyaconitine A can be separated from its neurotoxicity by the mechanism of action, [24] and the relatively wide therapeutic window of bulleyaconitine A suggests that its antinociception could be separated from its toxicity. [13] It means that bulleyaconitine A performs its ability by a specific pharmacological action in some way rather than its toxicity.…”

Section: Toxicities Of Bulleyaconitine Amentioning

confidence: 99%

Activities of Naturally Occurring Alkaloids Bulleyaconitine A

Zhai¹,

Zhou²,

Xu³

et al. 2017

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Aconitine disrupts serotonin neurotransmission via 5‐hydroxytryptamine receptor in zebrafish embryo

Chen

Wang

et al. 2020

J of Applied Toxicology

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Medicinal plants of the genus Aconitum are one of the most commonly used herbs in traditional medicine in East Asia to treat conditions related to the heart, pain, or inflammation. However, these herbs are also dangerous as accidental poisoning due to misuse is a recurring issue. These plants contain a number of diester‐diterpenoid alkaloid compounds and aconitine is the most abundant and active one. This study investigated neurotoxicity of aconitine to zebrafish embryos in early development in relation to serotonin regulation. Experimental results showed that aconitine exposure (1, 10, and 100 μM) increased frequency of coiling behavior in zebrafish embryos in a dose‐dependent manner and this effect can be triggered by either exposure to 5‐hydroxytryptamine 1A (5‐HT1A) receptor agonist (±)‐8‐hydroxy‐2‐(dipropylamino)tetralin (8‐OH‐DPAT) or overexpression of serotonin receptor 5‐htr1ab. At the same time, coiling behavior caused by aconitine exposure could be rescued by co‐exposure to 5‐HT1A receptor antagonist WAY‐100635 Maleate (WAY100635) and knockdown of 5‐htr1ab using morpholino. Exposure to aconitine also significantly increased serotonin receptor 5‐htr1ab and 5‐htr1bd gene expression at 24 h post fertilization (hpf), but decreased their expression and protein expression of the serotonin receptor at 96 hpf with the high dose. These results suggest that neurotoxicity caused by aconitine is mediated through the 5‐HT receptor.

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Aconitum-Derived Bulleyaconitine A Exhibits Antihypersensitivity Through Direct Stimulating Dynorphin A Expression in Spinal Microglia

Cited by 45 publications

References 79 publications

Mechanisms for therapeutic effect of bulleyaconitine A on chronic pain

Mechanisms for therapeutic effect of bulleyaconitine A on chronic pain

Activities of Naturally Occurring Alkaloids Bulleyaconitine A

Aconitine disrupts serotonin neurotransmission via 5‐hydroxytryptamine receptor in zebrafish embryo

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