title: Chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala.
abstract: Exacerbation of pain by chronic stress and comorbidity of pain with stress-related psychiatric disorders, including anxiety and depression, represent significant clinical challenges. However, the underlying mechanisms still remain unclear. Here, we investigated whether chronic forced swim stress (CFSS)-induced exacerbation of neuropathic pain is mediated by the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala (CeA). We first demonstrated that CFSS indeed produces both depressive-like behaviors and exacerbation of spared nerve injury (SNI)-induced mechanical allodynia in rats. Moreover, we revealed that CFSS induces both sensitization of basolateral amygdala (BLA) neurons and augmentation of long-term potentiation (LTP) at the BLA-CeA synapse and meanwhile, exaggerates both SNI-induced sensitization of CeA neurons and LTP at the parabrachial (PB)-CeA synapse. In addition, we discovered that CFSS elevates SNI-induced functional up-regulation of GluN2B-containing NMDA (GluN2B-NMDA) receptors in the CeA, which is proved to be necessary for CFSS-induced augmentation of LTP at the PB-CeA synapse and exacerbation of pain hypersensitivity in SNI rats. Suppression of CFSS-elicited depressive-like behaviors by antidepressants imipramine or ifenprodil inhibits the CFSS-induced exacerbation of neuropathic pain. Collectively, our findings suggest that CFSS potentiates synaptic efficiency of the BLA-CeA pathway, leading to the activation of GluN2B-NMDA receptors and sensitization of CeA neurons, which subsequently facilitate pain-related synaptic plasticity of the PB-CeA pathway, thereby exacerbating SNI-induced neuropathic pain. We conclude that chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the CeA.
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing, China.|Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Ming-Jia
authors.initials: MJ
authors.lastname: Li
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing, China.|Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Liu
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing, China.|Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing, China.|Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: You
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing, China.|Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China.
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Xing
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D066274:Central Amygdaloid Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005518:Food Preferences / Q000523:psychology; D006930:Hyperalgesia / Q000503:physiopathology; D008124:Locomotion / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009437:Neuralgia / Q000150:complications*; D009474:Neurons / Q000502:physiology; D017288:Pain Threshold / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000150:complications*; D013395:Sucrose; D013550:Swimming / Q000523:psychology; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D013395:Sucrose