Cross-talk between the colon epithelium, colon afferents and sympathetic neurons regulate pain in the normal and inflamed colon

结肠上皮、结肠传入神经和交感神经元之间的串扰调节正常和发炎结肠的疼痛

• 批准号: 10399623
• 负责人: Kathryn Marie Albers
• 金额: $ 45.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399623
• 关键词: Acute; Afferent Neurons; Biological Assay; Calcium; Calcium Signaling; Chemicals; Chronic; Colon; Colonic inflammation; Communication; Data; Disease; Electric Stimulation; Epithelial; Epithelial Cells; Fiber; Frequencies; Glutamates; Goals; Hypersensitivity; Image; Immune system; Inflammation; Inflammatory Bowel Diseases; Injury; Lead; Limb structure; Measures; Mechanics; Modeling; Motor Neurons; Mus; Nature; Neuromodulator; Neurons; Neurotransmitter Receptor; Neurotransmitters; Norepinephrine; Occupations; Opsin; Organism; Pain; Pain management; Peripheral; Peripheral Nervous System; Pharmacology; Phase; Physiological; Play; Preparation; Process; Proton Pump; Role; Serotonin; Signal Transduction; Sodium Dextran Sulfate; Spinal; Spinal Cord; Stimulus; Stress; Stretching; Sympathetic Ganglia; Symptoms; Synapses; System; Testing; Time; Visceral; Visceral pain; behavioral response; cell type; chronic pain; colorectal distension; dextran sulfate sodium induced colitis; experimental study; neuronal circuitry; novel; patch clamp; response; spinal nerve posterior root

SUMMARY Visceral pain is notoriously difficult to treat, often persisting long after the precipitating injury/disease is no longer evident. In this application we will explore a novel, multicellular peripheral circuit that we hypothesize explains many of the intractable features of chronic, visceral pain. We now know that epithelial-neuronal communication is widespread, with numerous epithelial cell types releasing neuroactive substances (e.g., ATP, ACh, 5HT, glutamate). This is particularly apparent in the colon where we have found that channelrhodopsin (ChR2) -induced activation of colon epithelial cells produces high frequency bursting of colon extrinsic primary afferent neurons (ExPAN’s), phenocopying physiologic stimuli and inducing robust behavioral responses (visceromotor responses (VMR), a validated assay of hypersensitivity). Building on these findings, new surprising data indicate colon epithelium also receives functional input from sympathetic neurons; activation of sympathetic projections to the colon induces large, phase-locked calcium signals in the epithelium. Closing the loop, we found that activation of ExPAN’s via colorectal distension (CRD) induces calcium signals in the post-ganglionic sympathetic neurons projecting to the colon, and that ChR2- induced activation of ExPAN’s induces cFos expression in these same neurons. That this multicellular circuit plays a role in visceral pain is supported further by preliminary data that shows that inflammation (acute and/or chronic) is correlated with increased signaling in all portions of this circuit. Thus, the goal of the proposed experiments is to test the hypothesis that persistent visceral hypersensitivity is due, at least in part, to amplification in an epithelial-ExPAN-sympathetic circuit such that it is possible to treat pain by breaking any limb of this feed-forward circuit (Fig.1). This hypothesis will be tested in 3 aims: Aim 1: Determine if persistent hypersensitivity induced in a model of IBD (DSS (dextran sulfate sodium)) is due to increased epithelial signaling and/or ExPAN excitability, Aim 2: Determine if DSS-induced inflammation increases the ability of ExPANs to activate sympathetic neurons in prevertebral sympathetic ganglion (PrSG) directly (via synapses in PrSG) or indirectly (via a spinal cord circuit) and, Aim 3 Determine the ability of sympathetic neurons to drive activity in epithelial cells in naïve mice and in the DSS model of IBD.

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