Preoperative Anxiety-induced Glucocorticoid Signaling Reduces GABAergic Markers in Spinal Cord and Promotes Postoperative Hyperalgesia by Affecting Neuronal PAS Domain Protein 4

Overview

Journal Mol Pain

Date 2019 May 2

PMID 31041873

Citations 6

Authors

Hao Wu

Yulin Huang

Xinyu Tian

Zuoxia Zhang

Ying Zhang

Yanting Mao

Chenchen Wang

Shuai Yang

Yue Liu

Wei Zhang

Zhengliang Ma

Affiliations

Soon will be listed here.

Abstract

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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References

Sabatini P, Krentz N, Zarrouki B, Westwell-Roper C, Nian C, Uy R . Npas4 is a novel activity-regulated cytoprotective factor in pancreatic β-cells. Diabetes. 2013; 62(8):2808-20. PMC: 3717850. DOI: 10.2337/db12-1527. View

Wang S, Lim G, Yang L, Sung B, Mao J . Downregulation of spinal glutamate transporter EAAC1 following nerve injury is regulated by central glucocorticoid receptors in rats. Pain. 2005; 120(1-2):78-85. DOI: 10.1016/j.pain.2005.10.015. View

Anacker C, Cattaneo A, Luoni A, Musaelyan K, Zunszain P, Milanesi E . Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis. Neuropsychopharmacology. 2013; 38(5):872-83. PMC: 3672002. DOI: 10.1038/npp.2012.253. View

Zhang Z, Wu H, Liu Y, Gu X, Zhang W, Ma Z . The GCs-SGK1-ATP Signaling Pathway in Spinal Astrocytes Underlied Presurgical Anxiety-Induced Postsurgical Hyperalgesia. Anesth Analg. 2018; 129(4):1163-1169. DOI: 10.1213/ANE.0000000000003682. View

Yowtak J, Wang J, Kim H, Lu Y, Chung K, Chung J . Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse. Pain. 2013; 154(11):2469-2476. PMC: 3816493. DOI: 10.1016/j.pain.2013.07.024. View

Spiegel I, Mardinly A, Gabel H, Bazinet J, Couch C, Tzeng C . Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs. Cell. 2014; 157(5):1216-29. PMC: 4089405. DOI: 10.1016/j.cell.2014.03.058. View

Asmundson G, Katz J . Understanding the co-occurrence of anxiety disorders and chronic pain: state-of-the-art. Depress Anxiety. 2009; 26(10):888-901. DOI: 10.1002/da.20600. View

Wang S, Lim G, Zeng Q, Sung B, Yang L, Mao J . Central glucocorticoid receptors modulate the expression and function of spinal NMDA receptors after peripheral nerve injury. J Neurosci. 2005; 25(2):488-95. PMC: 6725479. DOI: 10.1523/JNEUROSCI.4127-04.2005. View

Brennan T, Vandermeulen E, Gebhart G . Characterization of a rat model of incisional pain. Pain. 1996; 64(3):493-502. DOI: 10.1016/0304-3959(95)01441-1. View

10.

Ibi D, Takuma K, Koike H, Mizoguchi H, Tsuritani K, Kuwahara Y . Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. J Neurochem. 2008; 105(3):921-32. DOI: 10.1111/j.1471-4159.2007.05207.x. View

11.

Martinez V, Uceyler N, Ben Ammar S, Alvarez J, Gaudot F, Sommer C . Clinical, histological, and biochemical predictors of postsurgical neuropathic pain. Pain. 2015; 156(11):2390-2398. DOI: 10.1097/j.pain.0000000000000286. View

12.

Abdelhamid R, Kovacs K, Pasley J, Nunez M, Larson A . Forced swim-induced musculoskeletal hyperalgesia is mediated by CRF2 receptors but not by TRPV1 receptors. Neuropharmacology. 2013; 72:29-37. PMC: 3696409. DOI: 10.1016/j.neuropharm.2013.04.016. View

13.

Lin H, Tseng Y, Mao S, Chen P, Gean P . GABAA receptor endocytosis in the basolateral amygdala is critical to the reinstatement of fear memory measured by fear-potentiated startle. J Neurosci. 2011; 31(24):8851-61. PMC: 6622947. DOI: 10.1523/JNEUROSCI.0979-11.2011. View

14.

Drake-Baumann R . Activity-dependent modulation of inhibition in Purkinje cells by TrkB ligands. Cerebellum. 2006; 5(3):220-6. DOI: 10.1080/14734220600621344. View

15.

Cao J, Wang P, Tiwari V, Liang L, Lutz B, Shieh K . Short-term pre- and post-operative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception. Mol Pain. 2015; 11:73. PMC: 4667457. DOI: 10.1186/s12990-015-0077-3. View

16.

Longden T, Dabertrand F, Hill-Eubanks D, Hammack S, Nelson M . Stress-induced glucocorticoid signaling remodels neurovascular coupling through impairment of cerebrovascular inwardly rectifying K+ channel function. Proc Natl Acad Sci U S A. 2014; 111(20):7462-7. PMC: 4034203. DOI: 10.1073/pnas.1401811111. View

17.

Butler R, Finn D . Stress-induced analgesia. Prog Neurobiol. 2009; 88(3):184-202. DOI: 10.1016/j.pneurobio.2009.04.003. View

18.

Yun J, Koike H, Ibi D, Toth E, Mizoguchi H, Nitta A . Chronic restraint stress impairs neurogenesis and hippocampus-dependent fear memory in mice: possible involvement of a brain-specific transcription factor Npas4. J Neurochem. 2010; 114(6):1840-51. DOI: 10.1111/j.1471-4159.2010.06893.x. View

19.

Bloodgood B, Sharma N, Browne H, Trepman A, Greenberg M . The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition. Nature. 2013; 503(7474):121-5. PMC: 4169177. DOI: 10.1038/nature12743. View

20.

Drew G, Siddall P, Duggan A . Mechanical allodynia following contusion injury of the rat spinal cord is associated with loss of GABAergic inhibition in the dorsal horn. Pain. 2004; 109(3):379-388. DOI: 10.1016/j.pain.2004.02.007. View