Electroacupuncture Alleviates Mechanical Allodynia in a Rat Model of Complex Regional Pain Syndrome Type-I via Suppressing Spinal CXCL12/CXCR4 Signaling

Hu, Quanteng; Zheng, Xiaoli; Li, Xiaojie; Liu, Boyu; Yin, Chengyu; Li, Yuanyuan; Chen, Ruixiang; Wang, Jie; Liang, Yi; Shao, Xiaomei; Fang, Jianqiao; Liu, Boyi

doi:10.1016/j.jpain.2020.01.007

Cited by 31 publications

(42 citation statements)

References 40 publications

(47 reference statements)

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“…Based on a previous experience ( Ye et al, 2017 ; Cui et al, 2019 ; Hu et al, 2020 ), we performed sham EA manipulation to ensure the 5-HT 7 R is specific in EA antihyperalgesia. The results showed that 5-HT 7 R expression was not decreased in the IS + SEA group ( Figures 4A–D , 5A–D ), cAMP was not decreased ( Figures 6A,F ), and there was no statistical difference in p-PKA, p-ERK 1 / 2 , p-CREB, and c-Fos compared with the IS group ( Figures 6B–E,G–J ), indicating that sham EA had no effect on 5-HT 7 R and its related protein, and that EA was specific.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous investigation found EA shows a direct effect on nociceptive neurons ( Qu et al, 2020a , b ). In addition, several studies ( Han et al, 2015 ; Shao et al, 2016 ; Hu et al, 2020 ) suggested PKA and ERK 1 / 2 in the spinal dorsal horn might involve EA antihyperalgesia. However, the participation of PKA and ERK 1 / 2 in EA antihyperalgesia has not been well defined.…”

Section: Introductionmentioning

confidence: 99%

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Determining 5HT7R’s Involvement in Modifying the Antihyperalgesic Effects of Electroacupuncture on Rats With Recurrent Migraine

Liu

et al. 2021

Front. Neurosci.

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Electroacupuncture (EA) is widely used in clinical practice to relieve migraine pain. 5-HT7 receptor (5-HT7R) has been reported to play an excitatory role in neuronal systems and regulate hyperalgesic pain and neurogenic inflammation. 5-HT7R could influence phosphorylation of protein kinase A (PKA)- or extracellular signal-regulated kinase1/2 (ERK1/2)-mediated signaling pathways, which mediate sensitization of nociceptive neurons via interacting with cyclic adenosine monophosphate (cAMP). In this study, we evaluated the role of 5-HT7R in the antihyperalgesic effects of EA and the underlying mechanism through regulation of PKA and ERK1/2 in trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Hyperalgesia was induced in rats with dural injection of inflammatory soup (IS) to cause meningeal neurogenic inflammatory pain. Electroacupuncture was applied for 15 min every other day before IS injection. Von Frey filaments, tail-flick, hot-plate, and cold-plated tests were used to evaluate the mechanical and thermal hyperalgesia. Neuronal hyperexcitability in TNC was studied by an electrophysiological technique. The 5-HT7R antagonist (SB269970) or 5-HT7R agonist (AS19) was administered intrathecally before each IS application at 2-day intervals during the 7-day injection protocol. The changes in 5-HT7R and 5-HT7R-associated signaling pathway were examined by real-time polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) analyses. When compared with IS group, mechanical and thermal pain thresholds of the IS + EA group were significantly increased. Furthermore, EA prevented the enhancement of both spontaneous activity and evoked responses of second-order trigeminovascular neurons in TNC. Remarkable decreases in 5-HT7R mRNA expression and protein levels were detected in the IS + EA group. More importantly, 5-HT7R agonist AS19 impaired the antihyperalgesic effects of EA on p-PKA and p-ERK1/2. Injecting 5-HT7R antagonist SB-269970 into the intrathecal space of IS rats mimicked the effects of EA antihyperalgesia and inhibited p-PKA and p-ERK1/2. Our findings indicate that 5-HT7R mediates the antihyperalgesic effects of EA on IS-induced migraine pain by regulating PKA and ERK1/2 in TG and TNC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Determining 5HT7R’s Involvement in Modifying the Antihyperalgesic Effects of Electroacupuncture on Rats With Recurrent Migraine

Liu

et al. 2021

Front. Neurosci.

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“…MCC950 or corresponding vehicle was applied 1 h before the behavioral test. MCC950 was applied via lumbar catheterization as we described before [32]. Briefly, rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.).…”

Section: Drug Applicationmentioning

confidence: 99%

Expression profiling of spinal cord dorsal horn in a rat model of complex regional pain syndrome type-I uncovers potential mechanisms mediating pain and neuroinflammation responses

Chen

Yin

et al. 2020

J Neuroinflammation

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Background Complex regional pain syndrome type-I (CRPS-I) is a progressive and devastating pain condition. The mechanisms of CRPS-I still remain poorly understood. We aim to explore expression profiles of genes relevant to pain and neuroinflammation mechanisms involved in CRPS-I. Methods The rat chronic post-ischemic pain (CPIP) model that mimics human CRPS-I was established. RNA-sequencing (RNA-Seq), qPCR, Western blot, immunostaining, and pharmacological studies were used for profiling gene changes in ipsilateral spinal cord dorsal horn (SCDH) of CPIP model rat and further validation. Results CPIP rats developed persistent mechanical allodynia in bilateral hind paws, accompanied with obvious glial activation in SCDH. RNA-Seq identified a total of 435 differentially expressed genes (DEGs) in ipsilateral SCDH of CPIP rats. qPCR confirmed the expression of several representative genes. Functional analysis of DEGs identified that the most significantly enriched biological processes of upregulated genes include inflammatory and innate immune response. We further identified NLRP3 inflammasome expression to be significantly upregulated in SCDH of CPIP rats. Pharmacological blocking NLRP3 inflammasome reduced IL-1β overproduction, glial activation in SCDH as well as mechanical allodynia of CPIP rats. Conclusion Our study revealed that immune and inflammatory responses are predominant biological events in SCDH of CPIP rats. We further identified NLRP3 inflammasome in SCDH as a key contributor to the pain and inflammation responses in CPIP rats. Thus, our study provided putative novel targets that may help to develop effective therapeutics against CRPS-I.

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“…Based on previous experience [25,79,80], we also performed sham EA manipulation to ensure the 5-HT 7 R is speci c in EA antihyperalgesia. The results showed that 5-HT 7 R expression was not decreased in the Previous studies [44,45] show that the PKA-or ERK 1/2 -mediated signaling pathways are involved in the CFA-or CA induced long-lasting pain hypersensitivity through 5-HT 7 R. More expression of p-PKA or p-ERK 1/2 means more excitation of dura-sensitive trigeminal neurons and more sensitization of pain transducing receptors [81] [22].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous investigation found EA shows a direct effect on nociceptive neurons [23,24]. In addition, several studies [25][26][27] suggested PKA and ERK 1/2 in the spinal dorsal horn might involve EA antihyperalgesia.…”

Section: Introductionmentioning

confidence: 94%

Determining 5HT7R’s involvement in modifying the antihyperalgesic effects of electroacupuncture on rats with recurrent migraine

Liu

et al. 2020

Preprint

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Background: Electroacupuncture (EA) is widely used in clinical practice to relieve migraine pain. 5-HT7 receptor (5-HT7R) has been reported to play an excitatory role in neuronal systems and regulate hyperalgesic pain and neurogenic inflammation. 5-HT7R could influence Phosphorylation of protein kinase A (PKA)- or Extracellular signal-regulated kinase1/2 (ERK1/2)-mediated signaling pathways, which mediate sensitization of nociceptive neurons via interacting with cyclic Adenosine monophosphate (cAMP). In this study, we evaluated the role of 5-HT7R in the antihyperalgesic effects of EA and the underlying mechanism through regulation of PKA and ERK1/2 in trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Methods: Hyperalgesia was induced in rats with dural injection of inflammatory soup (IS) to cause meningeal neurogenic inflammatory pain. Electroacupuncture was applied for 15 minutes every other day before IS injection. Von Frey filaments, tail-flick, hot-plate, and cold-plated tests were used to evaluate the mechanical and thermal hyperalgesia. Neuronal hyperexcitability in TNC was studied by an electrophysiological technique. The 5-HT7R antagonist (SB269970) or 5-HT7R agonist (AS19) was administered intrathecally before each IS application at 2-days intervals during the 7-days injection protocol. The changes in 5-HT7R and 5-HT7R-mediated signaling pathway were examined by real time polymerase chain reaction (RT-PCR), Western blot, immunofluorescence and enzyme-linked immunosorbent assay (ELISA) analyses.Results: When compared with IS group, mechanical and thermal pain thresholds of the IS+EA group were significantly increased. Furthermore, EA prevented the enhancement of both spontaneous activity and evoked responses of second-order trigeminovascular neurons in TNC. Remarkable decreases in 5-HT7R mRNA expression and protein levels were detected in the IS+EA group. More importantly, 5-HT7R agonist AS19 impaired the antihyperalgesic effects of EA on p-PKA and p-ERK1/2. Injecting 5-HT7R antagonist SB-269970 into the intrathecal space of IS rats mimicked the effects of EA antihyperalgesia and inhibited p-PKA and p-ERK1/2. Conclusion: Our findings indicate that 5-HT7R mediates the antihyperalgesic effects of EA on IS-induced migraine pain by regulating PKA and ERK1/2 in TG and TNC.

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Electroacupuncture Alleviates Mechanical Allodynia in a Rat Model of Complex Regional Pain Syndrome Type-I via Suppressing Spinal CXCL12/CXCR4 Signaling

Cited by 31 publications

References 40 publications

Determining 5HT7R’s Involvement in Modifying the Antihyperalgesic Effects of Electroacupuncture on Rats With Recurrent Migraine

Determining 5HT7R’s Involvement in Modifying the Antihyperalgesic Effects of Electroacupuncture on Rats With Recurrent Migraine

Expression profiling of spinal cord dorsal horn in a rat model of complex regional pain syndrome type-I uncovers potential mechanisms mediating pain and neuroinflammation responses

Determining 5HT7R’s involvement in modifying the antihyperalgesic effects of electroacupuncture on rats with recurrent migraine

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Electroacupuncture Alleviates Mechanical Allodynia in a Rat Model of Complex Regional Pain Syndrome Type-I via Suppressing Spinal CXCL12/CXCR4 Signaling

Cited by 31 publications

References 40 publications

Determining 5HT7R’s Involvement in Modifying the Antihyperalgesic Effects of Electroacupuncture on Rats With Recurrent Migraine

Determining 5HT7R’s Involvement in Modifying the Antihyperalgesic Effects of Electroacupuncture on Rats With Recurrent Migraine

Expression profiling of spinal cord dorsal horn in a rat model of complex regional pain syndrome type-I uncovers potential mechanisms mediating pain and neuroinflammation responses

Determining 5HT7R’s involvement in modifying the antihyperalgesic effects of&nbsp;electroacupuncture on rats with recurrent migraine

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Determining 5HT7R’s involvement in modifying the antihyperalgesic effects of electroacupuncture on rats with recurrent migraine