Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats

Jiang, Ming; Zhang, Wei; Cheng, Chongxue; Ma, Zhengliang; Gu, Xiaoping

doi:10.1016/j.pbb.2015.04.015

Cited by 12 publications

(7 citation statements)

References 42 publications

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“…In line with the previous studies [12, 51], inhibition of spinal CaMKIIα by an i.t. injection of KN93 (45 nmol) attenuated behavioral hyperalgesia induced by fentanyl (n = 6 for each group, p < 0.001, two-way repeated measures ANOVA followed by Bonferroni multiple post-hoc comparisons; Fig 3A and 3B).…”

Section: Resultssupporting

confidence: 92%

CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats

Yin

Chen

et al. 2017

PLoS ONE

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Each of the lateral capsular division of central nucleus of amygdala(CeLC), periaqueductal gray (PAG), rostral ventromedial medulla(RVM) and spinal cord has been proved to contribute to the development of opioid-induced hyperalgesia(OIH). Especially, Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) in CeLC and spinal cord seems to play a key role in OIH modulation. However, the pain pathway through which CaMKIIα modulates OIH is not clear. The pathway from CeLC to spinal cord for this modulation was explored in the present study. Mechanical and thermal hyperalgesia were tested by von Frey test or Hargreaves test, respectively. CaMKIIα activity (phospho-CaMKIIα, p-CaMKIIα) was evaluated by western blot analysis. CaMKIIα antagonist (KN93) was micro-infused into CeLC, spinal cord or PAG, respectively, to evaluate its effect on behavioral hyperalgesia and p-CaMKIIα expression in CeLC, PAG, RVM and spinal cord. Then the underlying synaptic mechanism was explored by recording miniature excitatory postsynaptic currents (mEPSCs) on PAG slices using whole-cell voltage-clamp methods. Results showed that inhibition of CeLC, PAG or spinal CaMKIIα activity respectively by KN93, reversed both mechanical and thermal hyperalgesia. Microinjection of KN93 into CeLC decreased p-CaMKIIα expression in CeLC, PAG, RVM and spinal cord; while intrathecal KN93 can only block spinal but not CeLC CaMKIIα activity. KN93 injected into PAG just decreased p-CaMKIIα expression in PAG, RVM and spinal cord, but not in the CeLC. Similarly, whole-cell voltage-clamp recording found the frequency and amplitude of mEPSCs in PAG cells were decreased by KN93 added in PAG slice or micro-infused into CeLC in vivo. These results together with previous findings suggest that CaMKIIα may modulate OIH via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway.

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Section: Resultssupporting

confidence: 92%

CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats

Yin

Chen

et al. 2017

PLoS ONE

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“…We selected the dosage of remifentanil (0.04 mg/kg) based on our previous studies showing that this treatment could enhance postoperative hyperalgesia in rats. 8,19 As our results showed, treatments including sevoflurane anesthesia, sham surgery, and NS infusion had no influence on pain behavior, which is consistent with our previous studies 8,37 and other studies. 2,38 Both surgical incision and remifentanil infusion induced significant mechanical allodynia and thermal hyperalgesia.…”

Section: Discussionsupporting

confidence: 92%

Intraoperative electroacupuncture relieves remifentanil-induced postoperative hyperalgesia via inhibiting spinal glial activation in rats

et al. 2017

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BackgroundAccumulating studies have suggested that remifentanil, the widely-used opioid analgesic in clinical anesthesia, can activate the pronociceptive systems and enhance postoperative pain. Glial cells are thought to be implicated in remifentanil-induced hyperalgesia. Electroacupuncture is a complementary therapy to relieve various pain conditions with few side effects, and glial cells may be involved in its antinociceptive effect. In this study, we investigated whether intraoperative electroacupuncture could relieve remifentanil-induced postoperative hyperalgesia by inhibiting the activation of spinal glial cells, the production of spinal proinflammatory cytokines, and the activation of spinal mitogen-activated protein kinases.MethodsA rat model of remifentanil-induced postoperative hyperalgesia was used in this study. Electroacupuncture during surgery was conducted at bilateral Zusanli (ST36) acupoints. Behavior tests, including mechanical allodynia and thermal hyperalgesia, were performed at different time points. Astrocytic marker glial fibrillary acidic protein, microglial marker Iba1, proinflammatory cytokines, and phosphorylated mitogen-activated protein kinases in the spinal cord were detected by Western blot and/or immunofluorescence.ResultsMechanical allodynia and thermal hyperalgesia were induced by both surgical incision and remifentanil infusion, and remifentanil infusion significantly exaggerated and prolonged incision-induced pronociceptive effects. Glial fibrillary acidic protein, Iba1, proinflammatory cytokines (interleukin-1β and tumor necrosis factor-α), and phosphorylated mitogen-activated protein kinases (p-p38, p-JNK, and p-ERK1/2) were upregulated after surgical incision, remifentanil infusion, and especially after their combination. Intraoperative electroacupuncture significantly attenuated incision- and/or remifentanil-induced pronociceptive effects, spinal glial activation, proinflammatory cytokine upregulation, and phosphorylated mitogen-activated protein kinase upregulation.ConclusionsOur study suggests that remifentanil-induced postoperative hyperalgesia can be relieved by intraoperative electroacupuncture via inhibiting the activation of spinal glial cells, the upregulation of spinal proinflammatory cytokines, and the activation of spinal mitogen-activated protein kinases.

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“…With the increasing use of remifentanil as an analgesic in clinical anesthesia, lines of evidence have demonstrated that patients receiving remifentanil to control pain during operation may paradoxically become more sensitive to postoperative pain [21,22]. We selected the dosage of remifentanil (0.04 mg/kg) based on our previous studies [12,23], which showed that this dosage could enhance postoperative hyperalgesia in rats. The results in this study showed that treatments including sevo urane anesthesia, sham surgery, and NS infusion had no signi cant in uence on pain behavior, which is consistent with our previous studies [12,23] and other studies [24,25].…”

Section: Discussionmentioning

confidence: 99%

“…We selected the dosage of remifentanil (0.04 mg/kg) based on our previous studies [12,23], which showed that this dosage could enhance postoperative hyperalgesia in rats. The results in this study showed that treatments including sevo urane anesthesia, sham surgery, and NS infusion had no signi cant in uence on pain behavior, which is consistent with our previous studies [12,23] and other studies [24,25]. Both surgical incision and remifentanil infusion induced signi cant mechanical allodynia and thermal hyperalgesia.…”

Section: Discussionmentioning

confidence: 99%

SIRT2 overexpression alleviates remifentanil-induced postoperative hyperalgesia through microglia

Jiang

Zhu

Wang

et al. 2022

Preprint

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Background: Sirtuin 2 (SIRT2), a member of the mammalian sirtuin family, plays an important role in the pathogenesis of various neurological diseases. However, whether SIRT2 is involved in the regulation of remifentanil-induced postoperative hyperalgesia remains unclear. This study aimed to investigate the potential role of SIRT2 in regulating remifentanil-induced postoperative hyperalgesia.Methods: Remifentanil-induced postoperative hyperalgesia model was established in rats. SIRT2 was over-expressed by injecting recombinant adenoviruses. Nociceptive behaviors of mechanical allodynia and thermal hyperalgesia were measured with paw withdrawal mechanical threshold and paw withdrawal thermal latency, respectively. Iba1 (marker of microglia activation) and SIRT2 levels were detected with Western blot. Iba1 was also measured with immunofluorescence.Results: We found that SIRT2 was downregulated in the spinal cord in remifentanil-induced postoperative hyperalgesia rats. Intrathecal injection of a recombinant plasmid expressing SIRT2 markedly alleviated mechanical allodynia and thermal hyperalgesia in remifentanil-induced postoperative hyperalgesia rats. Iba1 were upregulated after surgical incision and remifentanil infusion, and the up-regulation was more obvious after the combination of surgical incision and remifentanil infusion. Moreover, our results showed that overexpression of SIRT2 inhibited the activation of the microglia in the spinal cord of remifentanil-induced postoperative hyperalgesia rats. Overexpression of SIRT2 significantly attenuated incision- and/or remifentanil induced pronociceptive effects and spinal microglia activation. Conclusions: Overexpression of SIRT2 alleviates remifentanil-induced postoperative hyperalgesia possibly via inhibition of spinal microglia activation. Therefore, SIRT2 may serve as a potential therapeutic target for treatment of neuropathic pain.Trial registration: Not applicable.

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Intrathecal injection of KN93 attenuates paradoxical remifentanil-induced postoperative hyperalgesia by inhibiting spinal CaMKII phosphorylation in rats

Cited by 12 publications

References 42 publications

CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats

CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats

Intraoperative electroacupuncture relieves remifentanil-induced postoperative hyperalgesia via inhibiting spinal glial activation in rats

SIRT2 overexpression alleviates remifentanil-induced postoperative hyperalgesia through microglia

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