Abstract
BackgroundCinobufagin 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.MethodsRat 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.ResultsCinobufagin, given intrathecally, dose-dependently attenuated mechanical allodynia in bone cancer pain rats, with the projected Emax of 90% MPE and ED50 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, β-endorphin 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/β-endorphin and mechanical antiallodynia in bone cancer pain were blocked by the pretreatment with the specific α7-nAChR antagonist methyllycaconitine.ConclusionsOur 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.
Highlights
Bufonis venenum (Chansu) is a traditional Chinese medicine that is prepared from the dried white secretion of the auricular glands and the skin glands of Bufo gargarizans Cantor or Bufo melanostictus Schneider
We recently discovered that microgliaderived IL-10 in neuropathic pain produced mechanical antiallodynia and thermal antihyperalgesia via autocrine secretion of β-endorphin which interacted with neuronal μopioid receptors [77, 78]
A total of 36 female bone cancer pain rats were divided into six groups and received intrathecal injection of the vehicle (10% dimethyl sulfoxide (DMSO) and 20% PEG400 in saline, 10 μL) and cinobufagin (1, 3, 10, 30, and 100 μg), respectively
Summary
The antiinflammatory and antinociceptive effects of Bufonis venenum and its purified bufadienolides have been extensively studied over the past years. Bufonis venenum has remarkable analgesic effect in patients with cancer pain including that from bone metastasis [22, 50], while it has been 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]. 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
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