A Study on the Mechanism of Cinobufagin in the Treatment of Paw Cancer Pain by Modulating Local<i>β</i>-Endorphin Expression<i>In Vivo</i>

Chen, Tao; Hu, Wei; He, Hui; Gong, Zipeng; Wang, Jing; Yu, Xiao-Chun; Ai, Ting; Zhan, Ling

doi:10.1155/2013/851256

Cited by 19 publications

(29 citation statements)

References 19 publications

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“…Moreover, the antinociceptive effect of Bufonis venenum or bufalin was blocked by the pretreatment with the opioid receptor antagonist naloxone or its peripheral form naloxone methiodide [9,10,74]. These studies suggested that Bufonis venenum and its effective ingredients produced antinociception through the β-endorphin/opioid receptor pathway [9,10].…”

Section: Introductionmentioning

confidence: 93%

“…The CRF receptor was associated with microglial expression of β-endorphin [8,33,40] and Bufonis venenum stimulated CRF expression [9,10]. Thus, the possible involvement of the CRF receptor in cinobufagin-induced mechanical antiallodynia was finally tested.…”

Section: Activation Of the α7-nachr Mediated Cinobufagininduced Spinamentioning

confidence: 99%

“…These findings suggested that Bufonis venenum induced antinociception via inhibition of NF-κB activation and subsequent expression of inflammatory cytokines [74,80,82]. However, administration of Bufonis venenum promoted the β-endorphin and corticotropin-releasing factor (CRF) levels in plasma, and immunostaining of β-endorphin and μopioid receptors in the tumor xenograft tissues of paw cancer pain mice; treatment with Bufonis venenum also stimulated the expression of β-endorphin and CRF in cultured primary lymphocytes [9,10]. Moreover, the antinociceptive effect of Bufonis venenum or bufalin was blocked by the pretreatment with the opioid receptor antagonist naloxone or its peripheral form naloxone methiodide [9,10,74].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, Bufonis venenum has remarkable analgesic effect in patients with cancer pain including that from bone metastasis [22,50], while it has been also served as an antitumor agent [2,12,25,48]. Preclinical studies showed that multiple daily intraperitoneal injections of Bufonis venenum (referred as to cinobufagin in the original paper) exerted mechanical antiallodynia and thermal antihyperalgesia in a mouse model of paw cancer pain [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…However, administration of Bufonis venenum promoted the β-endorphin and corticotropin-releasing factor (CRF) levels in plasma, and immunostaining of β-endorphin and μopioid receptors in the tumor xenograft tissues of paw cancer pain mice; treatment with Bufonis venenum also stimulated the expression of β-endorphin and CRF in cultured primary lymphocytes [9,10]. Moreover, the antinociceptive effect of Bufonis venenum or bufalin was blocked by the pretreatment with the opioid receptor antagonist naloxone or its peripheral form naloxone methiodide [9,10,74]. These studies suggested that Bufonis venenum and its effective ingredients produced antinociception through the β-endorphin/opioid receptor pathway [9,10].…”

Section: Introductionmentioning

confidence: 99%

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The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

Apryani

Ali

Wang

et al. 2020

J Neuroinflammation

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Background: Cinobufagin is the major bufadienolide of Bufonis venenum (Chansu), which has been traditionally used for the treatment of chronic pain especially cancer pain. The current study aimed to evaluate its antinociceptive effects in bone cancer pain and explore the underlying mechanisms. Methods: Rat bone cancer model was used in this study. The withdrawal threshold evoked by stimulation of the hindpaw was determined using a 2290 CE electrical von Frey hair. The β-endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Results: Cinobufagin, given intrathecally, dose-dependently attenuated mechanical allodynia in bone cancer pain rats, with the projected E max of 90% MPE and ED 50 of 6.4 μg. Intrathecal cinobufagin also stimulated the gene and protein expression of IL-10 and β-endorphin (but not dynorphin A) in the spinal cords of bone cancer pain rats. In addition, treatment with cinobufagin in cultured primary spinal microglia but not astrocytes or neurons stimulated the mRNA and protein expression of IL-10 and β-endorphin, which was prevented by the pretreatment with the IL-10 antibody but not β-endorphin antiserum. Furthermore, spinal cinobufagin-induced mechanical antiallodynia was inhibited by the pretreatment with intrathecal injection of the microglial inhibitor minocycline, IL-10 antibody, βendorphin antiserum and specific μ-opioid receptor antagonist CTAP. Lastly, cinobufagin-and the specific α-7 nicotinic acetylcholine receptor (α7-nAChR) agonist PHA-543613-induced microglial gene expression of IL-10/βendorphin and mechanical antiallodynia in bone cancer pain were blocked by the pretreatment with the specific α7-nAChR antagonist methyllycaconitine. Conclusions: Our results illustrate that cinobufagin produces mechanical antiallodynia in bone cancer pain through spinal microglial expression of IL-10 and subsequent β-endorphin following activation of α7-nAChRs. Our results also highlight the broad significance of the recently uncovered spinal microglial IL-10/β-endorphin pathway in antinociception.

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Section: Introductionmentioning

confidence: 93%

Section: Activation Of the α7-nachr Mediated Cinobufagininduced Spinamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

Apryani

Ali

Wang

et al. 2020

J Neuroinflammation

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Investigation of cytotoxic effect of the bufanolide steroid compound cinobufagin and its related underlying mechanism in brain cell models

Hsu

Lin

Liang

2021

J Biochem & Molecular Tox

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Cinobufagin, a bufadienolide of toad venom of Bufo bufo gargarizans, is used as a cardiotonic, central nervous system (CNS) respiratory agent, as well as an analgesic and anesthetic. However, several research showed that bufadienolide has a few side effects on the CNS, such as breathlessness or coma. Although cinobufagin was shown to display pharmacological effects in various models, the toxic effect of cinobufagin is elusive in brain cell models. The aim of this study was to explore whether cinobufagin affected viability, Ca 2+ homeostasis, and reactive oxygen species (ROS) production in Gibco ® Human Astrocyte (GHA) and HCN-2 neuronal cell line. In GHA cells but not in HCN-2 cells, cinobufagin (20-60 μM) induced [Ca 2+ ] i rises. In terms of cell viability, chelation of cytosolic Ca 2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid reduced cinobufagin-induced cytotoxicity in GHA cells. In GHA cells, cinobufagin-induced Ca 2+ entry was inhibited by 2-aminoethoxydiphenyl borate or SKF96365. In a Ca 2+ -free medium, treatment with thapsigargin or U73122 abolished cinobufagin-evoked [Ca 2+ ] i rises. Furthermore, treatment with N-acetylcysteine reversed ROS production and cytotoxicity in cinobufagin-treated GHA cells. Together, in GHA cells but not in HCN-2 cells cinobufagin caused cytotoxicity that was linked to preceding [Ca 2+ ] i rises by Ca 2+ influx via store-operated Ca 2+ entry and phospholipase C-dependent Ca 2+ release from the endoplasmic reticulum. Moreover, cinobufagin induced ROS-associated cytotoxicity.brain cell models Ca 2+ homeostasis, cinobufagin, cytotoxicity, ROS | INTRODUCTIONChan Su, a traditional herbal medicine, is prepared from the skin glands of toad venom Bufo bufo gargarizans Cantor. [1,2] The major active components in Chan Su are bufadienolides, such as bufalin, cinobufagin, and resibufogenin. Bufadienolides, a group of steroid hormones, were shown to block the adenosine triphosphatase sodium-potassium pump, Na + /K + -ATPase. [3][4][5] Bufadienolides displayed many pharmacological effects through Na + /K + -ATPase, such as reduction of inflammation, [6] enhancement of cardiac contractility, [7] and inhibition of tumor. [8] Furthermore, cinobufagin was shown to have pharmacological applications in cancer treatment and analgesic properties. [9,10] The chemical structure of bufadienolides has similarities to digoxin, which is used to treat various heart conditions. [4,11,12] However, it has been shown that bufadienolides exhibit cardiotoxic effects by competing with K + ions for the same binding site on the Na + /K + -ATPase pump. [4,11,12] © 2021 Wiley Periodicals LLC Cinobufagin was reported to induce cytotoxicity in various cell models. It has been shown that cinobufagin induced apoptosis in MCF-7 human breast cancer cells [13] and 143B human osteosarcoma cells, [14] caused autophagy in U2OS human osteosarcoma cells, [15] evoked cell cycle arrest in MDA-MB-231 human breast cancer cells, [16] and exerted antiproliferation in U266 human multiple myeloma cells. [17] In Ca ...

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Douleur, médecine chinoise et médecine factuelle : les grands essais récents

2015

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A Study on the Mechanism of Cinobufagin in the Treatment of Paw Cancer Pain by Modulating Localβ-Endorphin ExpressionIn Vivo

Cited by 19 publications

References 19 publications

The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

Investigation of cytotoxic effect of the bufanolide steroid compound cinobufagin and its related underlying mechanism in brain cell models

Douleur, médecine chinoise et médecine factuelle : les grands essais récents

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