The GCs-SGK1-ATP Signaling Pathway in Spinal Astrocytes Underlied Presurgical Anxiety-Induced Postsurgical Hyperalgesia

Zhang, Zuoxia; Wu, Hao; Liu, Yue; Gu, Xiaoping; Zhang, Wei; Ma, Zhengliang

doi:10.1213/ane.0000000000003682

Cited by 7 publications

(7 citation statements)

References 34 publications

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“…53,54 And our previous works have revealed that GCs can activate microglias and astrocytes in spinal cord, which contributes to postoperative hyperalgesia. 55,56 While in this study, we also found that CORT downregulated the GABAergic markers of neurons in vitro, indicating the direct effects of GC on neurons.…”

Section: Discussionsupporting

confidence: 59%

Preoperative anxiety-induced glucocorticoid signaling reduces GABAergic markers in spinal cord and promotes postoperative hyperalgesia by affecting neuronal PAS domain protein 4

Huang

Tian

et al. 2019

Mol Pain

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Preoperative anxiety is common in patients undergoing elective surgery and is closely related to postoperative hyperalgesia. In this study, a single prolonged stress model was used to induce preoperative anxiety-like behavior in rats 24 h before the surgery. We found that single prolonged stress exacerbated the postoperative pain and elevated the level of serum corticosterone. Previous studies have shown that glucocorticoid is associated with synaptic plasticity, and decreased spinal GABAergic activity can cause hyperalgesia in rodents. Here, single prolonged stress rats’ lumbar spinal cord showed reduced glutamic acid decarboxylase-65, glutamic acid decarboxylase-67, GABA type A receptor alpha 1 subunit, and GABA type A receptor gamma 2 subunit, indicating an impairment of GABAergic system. Furthermore, neuronal PAS domain protein 4 was also reduced in rats after single prolonged stress stimulation, which has been reported to promote GABAergic synapse development. Then, intraperitoneal injection of RU486 (a glucocorticoid receptor antagonist) rather than spironolactone (a mineralocorticoid receptor antagonist) was found to relieve single prolonged stress-induced hyperalgesia and reverse neuronal PAS domain protein 4 reduction and the impairment of GABAergic system. Furthermore, overexpressing neuronal PAS domain protein 4 could also restore the damage of GABAergic system caused by single prolonged stress while interfering with neuronal PAS domain protein 4 caused an opposite effect. Finally, after stimulation of rat primary spinal cord neurons with exogenous corticosterone in vitro, neuronal PAS domain protein 4 and GABAergic markers were also downregulated, and RU486 reversed that. Together, our results demonstrated that preoperative anxiety led to GABAergic system impairment in spinal cord and thus caused hyperalgesia due to glucocorticoid-induced downregulation of neuronal PAS domain protein 4.

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Section: Discussionsupporting

confidence: 59%

Preoperative anxiety-induced glucocorticoid signaling reduces GABAergic markers in spinal cord and promotes postoperative hyperalgesia by affecting neuronal PAS domain protein 4

Huang

Tian

et al. 2019

Mol Pain

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“…More recently, another study exploring the possible underlying mechanisms of glucocorticoids in presurgical anxiety-induced postsurgical pain found that SPS induced the upregulation of plasma corticosterone in rats and that the intraperitoneal application of corticosterone mimicked SPS-induced postsurgical hyperalgesia. Furthermore, they found that the expression of SGK1 and the concentration of ATP in the spinal cord were upregulated and that the inhibitor of SGK1 markedly decreased ATP release and attenuated pain-related behaviors (Zhang et al, 2019). Similarly, another study showed that chronic corticosterone exposure increased the level of phosphorylated SGK1 in a chronic corticosteroneinduced mouse model of anxiety/depression (Zhang et al, 2016).…”

Section: Sgk1 and Emotion-related Painmentioning

confidence: 98%

“…Recently, many studies have focused on the novel role of SGK1 in stress, depression, fear episodes, and anxiety (Luca et al, 2009;Anacker et al, 2013;Wei et al, 2016;Zhang et al, 2019). In the context of these psychiatric disorders, the expression of SGK1 has been demonstrated to be increased in animals and humans (Anacker et al, 2013;Yuan et al, 2016).…”

Section: Sgk1 and Emotion-related Painmentioning

confidence: 99%

“…An animal model was established to assess the mechanisms of presurgical anxietyinduced postsurgical hyperalgesia. The animal was exposed to a single-prolonged stress (SPS) procedure prior to a planter incisional surgery to induce presurgical anxiety-like behaviors (Liu et al, 2015;Sun et al, 2017;Zhang et al, 2019). It was found that glucocorticoids were involved in the development of presurgical anxiety-induced postsurgical pain (Sun et al, 2017).…”

Section: Sgk1 and Emotion-related Painmentioning

confidence: 99%

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Emerging Role of Serum Glucocorticoid-Regulated Kinase 1 in Pathological Pain

Liu

Zhang

et al. 2021

Front. Mol. Neurosci.

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Currently, the management of acute and chronic pain in clinical practice remains unsatisfactory due to the existence of limited effective treatments, and novel therapeutic strategies for pathological pain are urgently needed. In the past few decades, the role of serum and glucocorticoid-inducible kinase 1 (SGK1) in the development of pain and diurnal rhythms has been implicated in numerous studies. The expression levels of SGK1 mRNA and protein were found to be elevated in the spinal cord and brain in various pathological pain models. Blocking SGK1 significantly attenuated pain-like responses and the development of pathological pain. These studies provide strong evidence that SGK1 plays a role in the development of various types of pathological pain and that targeting SGK1 may be a novel therapeutic strategy for pain management. In this review article, we provide evidence from animal models for the potential role of SGK1 in the regulation of pathological pain caused by inflammation, nerve injury, psychiatric disorders, and chronic opioid exposure.

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“…Additionally, a number of rodent models have shown that stress alone can increase pain sensitivity, a phenomena referred to as stress-induced hyperalgesia [19,20]. However, few researchers have examined how exposure to acute stress immediately before an injury effects pain sensitization [21][22][23][24][25][26][27]. In addition, studies tend to use only one stressor, which can lead to contextualization of stress.…”

Section: Introductionmentioning

confidence: 99%

Exploring combat stress exposure effects on burn pain in a female rodent model

et al. 2022

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In the military, constant physiological and psychological stress encountered by Soldiers can lead to development of the combat and operational stress reaction (COSR), which can effect pain management. Similar effects are seen in other populations subjected to high levels of stress. Using a model of COSR, our lab recently showed that four weeks of stress prior to an injury increases pain sensitivity in male rats. With the roles of women in the military expanding and recent studies indicating sex differences in stress and pain processing, this study sought to investigate how different amounts of prior stress exposure affects thermal injury-induced mechanosensitivity in a female rat model of COSR. Adult female Sprague Dawley rats were exposed to the unpredictable combat stress (UPCS) procedure for either 2 or 4 weeks. The UPCS procedure included exposure to one stressor each day for four days. The stressors include: (1) sound stress for 30 min, (2) restraint stress for 4 h, (3) cold stress for 4 h, and (4) forced swim stress for 15 min. The order of stressors was randomized weekly. Mechanical and thermal sensitivity was tested twice weekly. After the UPCS procedure, a sub-set of rats received a thermal injury while under anesthesia. The development of mechanical allodynia and thermal hyperalgesia was examined for 14 days post-burn. UPCS exposure increased mechanosensitivity after two weeks. Interestingly, with more stress exposure, females seemed to habituate to the stress, causing the stress-induced changes in mechanosensitivity to decrease by week three of UPCS. If thermal injury induction occurred during peak stress-induced mechanosensitivity, after two weeks, this resulted in increased mechanical allodynia in the injured hind paw compared to thermal injury alone. This data indicates a susceptibility to increased nociceptive sensitization when injury is sustained at peak stress reactivity. Additionally, this data indicates a sex difference in the timing of peak stress. Post-mortem examination of the prefrontal cortex (PFC) showed altered expression of p-TrkB in 4-week stressed animals given a thermal injury, suggesting a compensatory mechanism. Future work will examine treatment options for preventing stress-induced pain to maintain the effectiveness and readiness of the Warfighter.

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The GCs-SGK1-ATP Signaling Pathway in Spinal Astrocytes Underlied Presurgical Anxiety-Induced Postsurgical Hyperalgesia

Abstract: These data suggested an important signaling pathway that affected the pain sensitivity after operation caused by presurgical anxiety.

Cited by 7 publications

References 34 publications

Preoperative anxiety-induced glucocorticoid signaling reduces GABAergic markers in spinal cord and promotes postoperative hyperalgesia by affecting neuronal PAS domain protein 4

Preoperative anxiety-induced glucocorticoid signaling reduces GABAergic markers in spinal cord and promotes postoperative hyperalgesia by affecting neuronal PAS domain protein 4

Emerging Role of Serum Glucocorticoid-Regulated Kinase 1 in Pathological Pain

Exploring combat stress exposure effects on burn pain in a female rodent model

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