Dezocine exhibits antihypersensitivity activities in neuropathy through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition

Wang, Yongxiang; Mao, Xiao-Fang; Li, Teng-Fei; Gong, Nian; Zhang, Mazhong

doi:10.1038/srep43137

Cited by 38 publications

(25 citation statements)

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“…Dezocine is first discovered by Pfizer for the treatment of perioperative pain [26]. Later reports demonstrate that dezocine exhibits anti-nociception effect in a rat neuropathic pain model [8], as well as antihypersensitivity in neuropathy by activating μ-opioid receptor in the spinal cord [27].…”

Section: Discussionmentioning

confidence: 99%

Dezocine attenuates neuropathic pain by inhibiting ERK1/2 signaling in rats

Shen

Sheng

et al. 2019

Preprint

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Background Neuropathic pain severely impacts patients’ life quality. Dezocine can be used for the treatment of pain. The present study intended to explore the effects of dezocine in chronic constriction injury (CCI) induced neuropathic pain as well as the possible responsible molecules in rats. Methods There were 3 subgroups, ie, control group, CCI group and dezocine+CCI group. The values of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in rats were determined by a dynamic plantar esthesiometer. The ipsilateral lumbar spinal cords in rats were extracted for the detection of protein levels of phosphorylated-mammalian target of rapamycin (p-mTOR) and p-extracellular signal-regulated kinase 1/2 (p-ERK1/2) by western blot analysis; and the mRNA and protein expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and cyclooxygenase-2 (COX-2) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results In comparison with control group, there were lower values of PWT and PWL in CCI group, which were partially reversed by dezocine. In addition, compared to control group, the expression levels of p-mTOR, p-ERK1/2, IL-6, TNF-α and COX-2 were upregulated by CCI, which were attenuated by dezocine. Conclusions In conclusion, the analgesic effect of dezocine on CCI induced neuropathic pain might be correlated with inhibiting of the p-mTOR and p-ERK1/2 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Dezocine attenuates neuropathic pain by inhibiting ERK1/2 signaling in rats

Shen

Sheng

et al. 2019

Preprint

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“…Once known as a mu opioid receptor antagonist and kappa opioid receptor agonist, dezocine has recently been recognized as a weak mu opioid receptor agonist and kappa opioid receptor antagonist, with an inhibitory effect on the re-uptake of noradrenalin and serotonin [ 10 , 11 , 17 , 18 ]. Several reports have suggested that dezocine possesses a potent analgesic effect, and thus, it has been used in perioperative pain management [ 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

Additive analgesic effect of dexmedetomidine and dezocine administered intrathecally in a mouse pain model

et al. 2018

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BackgroundIt is known that dexmedetomidine can reduce opioid requirements and that there is a synergistic effect when dexmedetomidine and morphine (a full mu opioid receptor agonist) are administered together. However, it was unclear whether a synergistic or additive effect would be observed when dexmedetomidine was co-administered with a partial mu opioid receptor agonist. The present study was designed to elucidate such effects by intrathecally co-administering dexmedetomidine and dezocine, a partial mu receptor agonist, in a mouse pain model.MethodsC57 mice (N = 165) were randomly divided into 19 groups. The tail flick test was adopted to measure the antinociceptive effects of the tested agents. The mice were divided into saline and drug groups to investigate the dose-dependent analgesic effects. Each drug was administered at fixed doses alone and in combination with one of three doses of a second drug.ResultsDezocine (0.3125 - 1.25 μg) and dexmedetomidine (0.04 - 1 μg) both enhanced the tail withdrawal latency in dose-dependent fashions. Dexmedetomidine (0.04 - 1 μg) enhanced the analgesic effect of dezocine. Dezocine (0.3125 - 1.25 μg) enhanced the analgesic effect of dexmedetomidine. Compared with the individual drug effects, the combined effects of dezocine (0.625 μg) and dexmedetomidine (0.04 μg) were more potent 15 - 60 min after injection, but they remained similar to the sum of the effects of the two individual drugs.ConclusionsDexmedetomidine and dezocine produce an additive analgesic effect on acute nociception when administered simultaneously.

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“…The hindpaw withdrawal threshold to mechanical stimuli was measured using a 2290CE electrical von Frey hair (IITC Life Science Inc., CA, USA) according to the previous study [46]. Neuropathic rats were acclimatized to the Plexiglas box on a metal grid for at least 30 minutes.…”

Section: Mechanical Allodynia Assessmentmentioning

confidence: 99%

Cynandione A alleviates neuropathic pain through spinal microglial interleukin-10/β-endorphin expression following α7 nicotinic acetylcholine receptor activation

Han

Yin

Wang

et al. 2020

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Abstract Background Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antihypersensitivity effects in neuropathic pain. This study sought to explore the target molecule and mechanisms underlying cynandione A mechanical antiallodynia, particularly related to the spinal glial expression of IL-10/β-endorphin, cAMP/PKA/p38/CREB signaling and α7 nicotinic acetylcholine receptor (α7 nAChR) activation. Methods IL-10 and β-endorphin in the spinal cord of spinal nerve ligation-induced neuropathic pain rats and cultured primary microglia were assessed by qRT-PCR and ELISA assays. Double immunofluorescence staining of IL-10, β-endorphin with glial and neuronal cellular biomarkers was also conducted in the spinal cord and cultured primary microglia. Microglial phosphorylation of PKA, p38, CREB and STAT3 were detected using western blot. Results Cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased IL-10 and β-endorphin (but not dynorphin A) expression in the spinal cords and cultured primary microglia. The IL-10 antibody attenuated cynandione A-induced spinal or microglial gene expression of β-endorphin and mechanical antiallodynia, whereas the β-endorphin antiserum blocked cynandione A-induced mechanical antiallodynia but not spinal or microglial IL-10 gene expression. The α7 nAChR antagonist methyllycaconitine significantly declined cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated microglial phosphorylation of PKA, p38 and CREB, which was inhibited by methyllycaconitine. Treatment with the adenylyl cyclase inhibitor DDA, PKA inhibitor H-89, p38 inhibitor SB203580 and CREB inhibitor KG501 attenuated cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, H-89 and the IL-10 antibody. The STAT3 inhibitor NSC74859 weakened cynandione A-induced mechanical antiallodynia and spinal expression of β-endorphin. Conclusion Our results illustrate that cynandione A produces mechanical antiallodynia through spinal microglial expression of IL-10 via the cAMP/PKA/p38/CREB signaling and subsequent β-endorphin expression via the IL-10/STAT3 signaling, following α7 nAChR activation.

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Dezocine exhibits antihypersensitivity activities in neuropathy through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition

Cited by 38 publications

References 50 publications

Dezocine attenuates neuropathic pain by inhibiting ERK1/2 signaling in rats

Dezocine attenuates neuropathic pain by inhibiting ERK1/2 signaling in rats

Additive analgesic effect of dexmedetomidine and dezocine administered intrathecally in a mouse pain model

Cynandione A alleviates neuropathic pain through spinal microglial interleukin-10/β-endorphin expression following α7 nicotinic acetylcholine receptor activation

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