Low frequency electroacupuncture alleviates neuropathic pain by activation of spinal microglial IL-10/β-endorphin pathway

Ali, Usman; Apryani, Evhy; Wu, Haiyun; Mao, Xiao-Fang; Líu, Hao; Wang, Yongxiang

doi:10.1016/j.biopha.2020.109898

Cited by 40 publications

(27 citation statements)

References 60 publications

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“…These results together reveal that cynandione A produces antinociception through α7 nAChR activation. The results further highlight the broad signi cance of the newly discovered spinal glial IL-10/β-endorphin pathway in pain modulation, which is associated with electroacupuncture-, GLP-1 receptor-, GPR40-and α7 nAChR-induced antinociception [10][11][12]. On the other hand, activation of α7 nAChR induces marked antineuroin amation by inhibiting the expression of proin ammatory cytokines such as IL-1β, IL-6 and TNF-α [53,54].…”

Section: Cynandione a Stimulated Il-10 And β-Endorphin Expression In mentioning

confidence: 99%

“…Intrathecal injection of IL-10 produced mechanical antiallodynia and thermal antihyperalgesia through spinal microglial expression of β-endorphin [9]. Furthermore, the spinal glial IL-10 and β-endorphin pathway has been revealed to be associated with the antinociceptive effects of electroacupuncture and the agonists of the glucagon-like peptide-1 (GLP-1) receptor and G proteincoupled receptor 40 (GPR40) in rodent models of neuropathic pain induced by spinal nerve ligation [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Cynandione a Stimulated Il-10 And β-Endorphin Expression In mentioning

confidence: 99%

Section: Introductionmentioning

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

Preprint

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“…This could be partially associated with the suppression of proinflammatory cytokines (e.g., TNF- α and IL-1 β ) and the stimulation of IL-10 in the spinal cord. IL-10, produced by the spinal cord, is the key anti-inflammatory cytokine for relieving both inflammatory pain [ 68 , 69 ] and neuropathic pain [ 70 ]. Paclitaxel significantly activates both microglia and astrocytes and increases the expression of inflammatory cytokines (IL-1 β and TNF- α ) in the lumbar spinal cord.…”

Section: Central Sensitization In Pain Transmission and Modulationmentioning

confidence: 99%

The Role of Neuroglial Crosstalk and Synaptic Plasticity-Mediated Central Sensitization in Acupuncture Analgesia

et al. 2021

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Although pain is regarded as a global public health priority, analgesic therapy remains a significant challenge. Pain is a hypersensitivity state caused by peripheral and central sensitization, with the latter considered the culprit for chronic pain. This study summarizes the pathogenesis of central sensitization from the perspective of neuroglial crosstalk and synaptic plasticity and underlines the related analgesic mechanisms of acupuncture. Central sensitization is modulated by the neurotransmitters and neuropeptides involved in the ascending excitatory pathway and the descending pain modulatory system. Acupuncture analgesia is associated with downregulating glutamate in the ascending excitatory pathway and upregulating opioids, 𝛾-aminobutyric acid, norepinephrine, and 5-hydroxytryptamine in the descending pain modulatory system. Furthermore, it is increasingly appreciated that neurotransmitters, cytokines, and chemokines are implicated in neuroglial crosstalk and associated plasticity, thus contributing to central sensitization. Acupuncture produces its analgesic action by inhibiting cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, and upregulating interleukin-10, as well as modulating chemokines and their receptors such as CX3CL1/CX3CR1, CXCL12/CXCR4, CCL2/CCR2, and CXCL1/CXCR2. These factors are regulated by acupuncture through the activation of multiple signaling pathways, including mitogen-activated protein kinase signaling (e.g., the p38, extracellular signal-regulated kinases, and c-Jun-N-terminal kinase pathways), which contribute to the activation of nociceptive neurons. However, the responses of chemokines to acupuncture vary among the types of pain models, acupuncture methods, and stimulation parameters. Thus, the exact mechanisms require future clarification. Taken together, inhibition of central sensitization modulated by neuroglial plasticity is central in acupuncture analgesia, providing a novel insight for the clinical application of acupuncture analgesia.

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“…(47) yapmış oldukları çalışmalarda balıklara asetik asit ile ağrı modeli oluşturmuş ve bunu davranış testleri ile de desteklemişlerdir. Bunun yanı sıra balıklara morfin gibi ekzojen opioidler vererek ağrının opioidler aracılığıyla azaltılabildiğini ve yine aynı çalışmalarda balıklara opioid antagonisti olan nalokson vererek morfin etkisinin ortadan kaldırıldığında balıkların yine aynı ya da yakın ağrıları hissettiğini ortaya koyarak balıkların ağrı çalışmaları için uygun bir model olduğunu ortaya koymuşlardır(47).Farmakolojik olmayan ağrı tedavilerinin analjezik etkilerinin, endojen opioid peptidleri etkilediği belirtilmiştir(48,49). Bu nedenle ağrının giderilmesi amacıyla bir kısmı farmakolojik olmayan tedavi denemeleri bulunmaktadır.…”

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“…Nöral endojen opioid sistemi, ağrının yönetiminde anahtar bir rol oynar ve akupunktur veya elektro-akupunkturla indüklenen analjezinin aracılığında çok önemlidir. Çalışmalar, düşük frekanslı elektro-akupunkturun Experimed 2021; 11(1):[49][50][51][52][53][54][55][56] Cansız ve ark. Endojen Opioidlerin Ağrı Mekanizması Üzerine Etkileri sırasıyla μ-opioid, δ-opioid ve FQ (NOP) reseptörleriyle etkileşime giren β-endorfin, enkefalin ve nosiseptin ekspresyonunu artırdığını ortaya koymuştur.…”

unclassified

Effects of Endogenous Opioids on Pain Mechanism

Cansız¹,

Emekli-Alturfan²,

Alturfan³

2021

Experimed

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Low frequency electroacupuncture alleviates neuropathic pain by activation of spinal microglial IL-10/β-endorphin pathway

Cited by 40 publications

References 60 publications

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

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

The Role of Neuroglial Crosstalk and Synaptic Plasticity-Mediated Central Sensitization in Acupuncture Analgesia

Effects of Endogenous Opioids on Pain Mechanism

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