Neuropathic Pain-induced Depression: the Role of mPFC Endocannabinoids

神经性疼痛诱发的抑郁症：mPFC 内源性大麻素的作用

• 批准号: 10440264
• 负责人: Bin Pan
• 金额: $ 37.48万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440264
• 关键词: 2-arachidonylglycerol; Absence of pain sensation; Acute; Acute Pain; Address; Adverse effects; Affective; Anatomy; Animals; Antidepressive Agents; Area; Behavior; Behavioral; Binding; Biological Assay; Brain; CNR1 gene; Chronic; Chronic Phase; Chronic stress; Clinical Research; Coupled; Data; Development; Disease; Down-Regulation; Electrophysiology (science); Elements; Endocannabinoids; Enzymes; Female; Fluoxetine; Foundations; Functional disorder; GTP-Binding Proteins; Gene Activation; Genetically Modified Animals; Goals; Hyperactivity; Immediate-Early Genes; Injections; Interneurons; Lead; Link; Mass Spectrum Analysis; Measures; Medial; Mental Depression; Modeling; Molecular; Nature; Neuraxis; Neurons; Neuropharmacology; Nociception; Opioid; Pain; Pathway interactions; Peripheral; Peripheral nerve injury; Persistent pain; Pharmacogenetics; Phase; Physiological; Prefrontal Cortex; Presynaptic Terminals; Process; Production; Public Health; Radiolabeled; Rattus; Regulation; Reporter; Research; Role; Signal Pathway; Signal Transduction; Slice; Spinocerebellar Tracts; Stress; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Thalamic structure; Therapeutic; Time; Transgenic Organisms; base; beta-arrestin; biopsychosocial; chronic pain; chronic pain patient; chronic painful condition; depression model; desensitization; effective intervention; endocannabinoid signaling; endogenous cannabinoid system; experimental study; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; insight; intraperitoneal; male; nerve injury; nerve supply; non-opioid analgesic; novel; novel therapeutics; painful neuropathy; preclinical study; prevent; programs; receptor downregulation; relating to nervous system; selective prevention; somatosensory; synaptic function; treatment strategy

Chronic pain is a major public health challenge that is inadequately addressed. The neural substrate of chronic pain includes disruption of numerous central nervous system (CNS) processes, and depression is a common consequence of chronic pain. The medial prefrontal cortex (mPFC) is a key brain area that regulates depres- sion, and the development of depression has been linked to disrupted synaptic function in the mPFC involving signaling through the endocannabinoid (eCB) system. Additionally, anatomical and electrophysiological studies show that afferent nociceptive pathways connect to the mPFC. We hypothesize that acute pain initially induces excess CB1R activation that eventually leads to CB1R downregulation, resulting in elevated GABAergic inner- vation of mPFC pyramidal neurons that persists as a chronic phase of reduced mPFC activity, with the final result being behavioral depression. This hypothesis is supported by preliminary data that reveal increased ac- tivity of mPFC pyramidal neurons and elevated 2-arachidonoylglycerol during the acute phase of nerve injury pain, and chronically desensitized CB1Rs that results in deactivation of mPFC pyramidal neurons, and deacti- vation of mPFC pyramidal neurons that cause depression-like behavior in animals. The proposed experiments will substantiate these promising findings, probe mechanistic details, and explore possible therapies. Specifi- cally, Aim 1 experiments will identify time courses of eCB signaling, mPFC activity, and depression-like behav- ior at early and late phases of neuropathic pain. Aim 2 will examine the state of mPFC synaptic function after initiation of pain and the causal linkage between eCB levels and synaptic function under these conditions. Fi- nally, Aim 3 will use diverse approaches to modulate this signaling pathway in order to verify the mechanistic findings of Aim 1 and 2, and to lay the groundwork for potential therapeutic strategies. Completion of the pro- posed project will not only generate new insights into the genesis of depression in neuropathic pain, but also may provide the proof-of-concept foundation for novel antidepressant treatments based on selective prevention or reversal of pain-induced CNS synaptic plasticity.

慢性疼痛是一项未得到充分解决的重大公共卫生挑战。慢性的神经基质

项目成果

Repetitive Mild Traumatic Brain Injury in Rats Impairs Cognition, Enhances Prefrontal Cortex Neuronal Activity, and Reduces Pre-synaptic Mitochondrial Function.

• DOI: 10.3389/fncel.2021.689334
• 发表时间: 2021
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Feng Y;Li K;Roth E;Chao D;Mecca CM;Hogan QH;Pawela C;Kwok WM;Camara AKS;Pan B
• 通讯作者: Pan B