scholarly journals Tiam1-mediated synaptic plasticity drives comorbid depressive symptoms in chronic pain

2021 ◽  
Author(s):  
Qin Ru ◽  
Yungang Lu ◽  
Ali Bin Saifullah ◽  
Francisco A Blanco ◽  
Changqun Yao ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Synaptic Plasticity ◽  
Depressive Symptoms ◽  
Molecular Mechanisms ◽  
Anterior Cingulate ◽  
Functional Plasticity ◽  
Cytoskeleton Reorganization ◽  
Antidepressant Effects ◽  
Functional Remodeling ◽  
Key Factor

Chronic pain and depression are frequently comorbid and ketamine has emerged as a potentially promising therapy. But the molecular mechanisms underlying comorbid depressive symptoms in chronic pain and ketamine antidepressant effects remain elusive. Here, we show that Tiam1 orchestrates synaptic structural and functional remodeling in anterior cingulate cortex (ACC) neurons via actin cytoskeleton reorganization and synaptic NMDAR stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. Ketamine induces sustained antidepressant effects in chronic pain by blocking Tiam1-mediated synaptic structural and functional plasticity in ACC neurons. Our results reveal Tiam1 as a key factor in the pathophysiology of chronic pain-induced depression and in the sustained antidepressant effects of ketamine in ACC neurons.

Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain

2016 ◽  
Vol 17 (8) ◽  
pp. 485-496 ◽  
Author(s):  
Tim V. P. Bliss ◽  
Graham L. Collingridge ◽  
Bong-Kiun Kaang ◽  
Min Zhuo
Keyword(s):  
Chronic Pain ◽  
Synaptic Plasticity ◽  
Anterior Cingulate Cortex ◽  
Cingulate Cortex ◽  
Anterior Cingulate

scholarly journals S-Ketamine Exerts Antidepressant Effects by Regulating Rac1 Gtpase Mediated Synaptic Plasticity in the Hippocampus of Stressed Rats

2021 ◽  
Author(s):  
Xianlin Zhu ◽  
Fan Zhang ◽  
Yufeng You ◽  
Hongbai Wang ◽  
Su Yuan ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Electrophysiological Study ◽  
Transmission Function ◽  
Long Term Potentiation ◽  
Neuronal Morphology ◽  
Antidepressant Effect ◽  
Mild Stress ◽  
Antidepressant Effects ◽  
Expression And Activity

Abstract Clinical studies have found that ketamine has a rapid and lasting antidepressant effect, especially in the case of patients with major depressive disorder (MDD). The molecular mechanisms, however, remain unclear. In this study, we observe the effects of S-Ketamine on the expression of Rac1, neuronal morphology, and synaptic transmission function in the hippocampus of stressed rats. Chronic unpredictable mild stress (CUMS) was used to construct stressed rats. The rats were given a different regimen of ketamine (20mg/kg, i.p.) and Rac1 inhibitor NSC23766 (50µg, ICV) treatment. The depression-like behavior of rats was evaluated by sucrose preference test and open-field test. The protein expression of Rac1, Glur1, synapsin1, and PSD95 in the hippocampus was detected by Western blot. Pull-down analysis was used to examine the activity of Rac1. Golgi staining and electrophysiological study were used to observe the neuronal morphology and long-term potentiation (LTP). Our results showed that ketamine can up-regulate the expression and activity of Rac1; increase the spine density and the expression of synaptic-related proteins such as Glur1, Synapsin1, and PSD95 in the hippocampus of stressed rats; reduce the CUMS-induced LTP impairments; and consequently improve depression-like behavior. However, Rac1 inhibitor NSC23766 could have effectively reversed ketamine-mediated changes in the hippocampus of rats and counteracted its antidepressant effects. The specific mechanism of S-ketamine's antidepressant effect may be related to the up-regulation of the expression and activity of Rac1 in the hippocampus of stressed rats, thus enhancing synaptic plasticity.

scholarly journals Immune Actions on the Peripheral Nervous System in Pain

2021 ◽  
Vol 22 (3) ◽  
pp. 1448
Author(s):  
Jessica Aijia Liu ◽  
Jing Yu ◽  
Chi Wai Cheung
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Process Integration ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Lipid Mediators ◽  
Cellular Changes

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

scholarly journals Ketamine—50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms

2021 ◽  
Vol 73 (2) ◽  
pp. 323-345
Author(s):  
Samuel Kohtala
Keyword(s):  
Traumatic Stress ◽  
Molecular Mechanisms ◽  
Post Traumatic Stress ◽  
Active Metabolites ◽  
The Past ◽  
Antidepressant Effects ◽  
Post Traumatic ◽  
Pharmacologically Active ◽  
Dose Dependent ◽  
Different Doses

AbstractOver the past 50 years, ketamine has solidified its position in both human and veterinary medicine as an important anesthetic with many uses. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder. The discovery of the rapid-acting antidepressant effects of ketamine has resulted in a surge of interest towards understanding the precise mechanisms driving its effects. Indeed, ketamine may have had the largest impact for advancements in the research and treatment of psychiatric disorders in the past few decades. While intense research efforts have been aimed towards uncovering the molecular targets underlying ketamine’s effects in treating depression, the underlying neurobiological mechanisms remain elusive. These efforts are made more difficult by ketamine’s complex dose-dependent effects on molecular mechanisms, multiple pharmacologically active metabolites, and a mechanism of action associated with the facilitation of synaptic plasticity. This review aims to provide a brief overview of the different uses of ketamine, with an emphasis on examining ketamine’s rapid antidepressant effects spanning molecular, cellular, and network levels. Another focus of the review is to offer a perspective on studies related to the different doses of ketamine used in antidepressant research. Finally, the review discusses some of the latest hypotheses concerning ketamine’s action.

scholarly journals Chronic Pain is Associated With Reduced Sympathetic Nervous System Reactivity During Simple and Complex Walking Tasks: Potential Cerebral Mechanisms

2021 ◽  
Vol 5 ◽  
pp. 247054702110302
Author(s):  
Taylor D. Yeater ◽  
David J. Clark ◽  
Lorraine Hoyos ◽  
Pedro A. Valdes-Hernandez ◽  
Julio A. Peraza ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Anterior Cingulate Cortex ◽  
Gray Matter ◽  
Dual Task ◽  
Brain Region ◽  
Skin Conductance Level ◽  
Cingulate Cortex ◽  
Anterior Cingulate ◽  
Autonomic Responses ◽  
The Difference

Background Autonomic dysregulation may lead to blunted sympathetic reactivity in chronic pain states. Autonomic responses are controlled by the central autonomic network (CAN). Little research has examined sympathetic reactivity and associations with brain CAN structures in the presence of chronic pain; thus, the present study aims to investigate how chronic pain influences sympathetic reactivity and associations with CAN brain region volumes. Methods Sympathetic reactivity was measured as change in skin conductance level (ΔSCL) between a resting reference period and walking periods for typical and complex walking tasks (obstacle and dual-task). Participants included 31 people with (n = 19) and without (n = 12) chronic musculoskeletal pain. Structural 3 T MRI was used to determine gray matter volume associations with ΔSCL in regions of the CAN (i.e., brainstem, amygdala, insula, and anterior cingulate cortex). Results ΔSCL varied across walking tasks (main effect p = 0.036), with lower ΔSCL in chronic pain participants compared to controls across trials 2 and 3 under the obstacle walking condition. ΔSCL during typical walking was associated with multiple CAN gray matter volumes, including brainstem, bilateral insula, amygdala, and right caudal anterior cingulate cortex (p’s < 0.05). The difference in ΔSCL from typical-to-obstacle walking were associated with volumes of the midbrain segment of the brainstem and anterior segment of the circular sulcus of the insula (p’s < 0.05), with no other significant associations. The difference in ΔSCL from typical-to-dual task walking was associated with the bilateral caudal anterior cingulate cortex, and left rostral cingulate cortex (p’s < 0.05). Conclusions Sympathetic reactivity is blunted during typical and complex walking tasks in persons with chronic pain. Additionally, blunted sympathetic reactivity is associated with CAN brain structure, with direction of association dependent on brain region. These results support the idea that chronic pain may negatively impact typical autonomic responses needed for walking performance via its potential impact on the brain.

scholarly journals Pra-C exerts analgesic effect through inhibiting microglial activation in anterior cingulate cortex in complete Freund’s adjuvant-induced mouse model

2021 ◽  
Vol 17 ◽  
pp. 174480692199093
Author(s):  
Dan-jie Su ◽  
Long-fei Li ◽  
Sai-ying Wang ◽  
Qi Yang ◽  
Yu-jing Wu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Mouse Model ◽  
Anterior Cingulate Cortex ◽  
Analgesic Effect ◽  
Microglial Activation ◽  
Cingulate Cortex ◽  
Anterior Cingulate ◽  
Freund’S Adjuvant ◽  
Complete Freund's Adjuvant ◽  
Freund's Adjuvant

Chronic pain is highly prevalent worldwide and severely affects daily lives of patients and family members. Praeruptorin C (Pra-C) is a main active ingredient derived from Peucedanum praeruptorum Dunn, traditionally used as antibechic, anti-bronchitis and anti-hypertension drug. Here, we evaluated the effects of Pra-C in a chronic inflammatory pain mouse model induced by complete Freund’s adjuvant (CFA) injection. Pra-C (3 mg/kg) treatment for just 3 days after CFA challenge relieved CFA-induced mechanical allodynia and hindpaw edema in mice. In the anterior cingulate cortex (ACC), Pra-C treatment inhibited microglia activation and reduced levels of proinflammatory cytokines, TNF-α and IL-1β, and suppressed upregulation of glutamate receptors caused by CFA injection. In addition, Pra-C attenuated neuronal hyperexcitability in ACC of CFA-injected mice. In vitro studies confirmed the analgesic effect of Pra-C was due to its inhibitory ability on microglial activation. In conclusion, Pra-C administration had a certain effect on relieving chronic pain by inhibiting microglial activation, attenuating proinflammatory cytokine releasing and regulating excitatory synaptic proteins in the ACC of the CFA-injected mice.

scholarly journals Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

2021 ◽  
Author(s):  
Joshua S. Siegel ◽  
Ben J. A. Palanca ◽  
Beau M. Ances ◽  
Evan D. Kharasch ◽  
Julie A. Schweiger ◽  
...  
Keyword(s):  
Depressive Symptoms ◽  
Limbic System ◽  
Anterior Cingulate ◽  
Sustained Remission ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Open Label ◽  
Subgenual Anterior Cingulate Cortex ◽  
Post Infusion ◽  
Resistant Depression

AbstractKetamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.ClinicalTrials.gov: Treatment Resistant Depression (Pilot), NCT01179009.

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