Painful Nerve Injury Decreases Resting Cytosolic Calcium Concentrations in Sensory Neurons of Rats

2005 ◽  
Vol 102 (6) ◽  
pp. 1217-1225 ◽  
Author(s):  
Andreas Fuchs ◽  
Philipp Lirk ◽  
Cheryl Stucky ◽  
Stephen E. Abram ◽  
Quinn H. Hogan
Keyword(s):  
Nerve Injury ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Sensory Information ◽  
Cytosolic Calcium ◽  
Skin Incision ◽  
Cellular Level ◽  
Spinal Nerve ◽  
Control Group

Background Neuropathic pain is difficult to treat and poorly understood at the cellular level. Although cytoplasmic calcium ([Ca]c) critically regulates neuronal function, the effects of peripheral nerve injury on resting sensory neuronal [Ca]c are unknown. Methods Resting [Ca]c was determined by microfluorometry in Fura-2 AM-loaded neurons dissociated from dorsal root ganglia of animals with hyperalgesia to mechanical stimulation after spinal nerve ligation and section (SNL) at the fifth and sixth lumbar (L5 and L6) levels and from animals after skin incision alone (control group). Axotomized neurons from the L5 dorsal root ganglia were examined separately from adjacent L4 neurons that share the sciatic nerve with degenerating L5 fibers. Results After SNL, large (34 mum or larger) neurons from the L4 ganglion showed a 29% decrease in resting [Ca]c, whereas those from the L5 ganglion showed a 54% decrease. Small neurons only showed an effect of injury in the axotomized L5 neurons, in which resting [Ca]c decreased by 30%. A decrease in resting [Ca]c was not seen in neurons isolated from rats in which hyperalgesia did not develop after SNL. In separate experiments, SNL reduced resting [Ca]c in capsaicin-insensitive neurons of the L5 ganglion by 60%, but there was no change in neurons from L4. Resting [Ca]c of capsaicin-sensitive neurons was not affected by injury in either ganglion. SNL injury decreased the proportion of neurons sensitive to capsaicin in the L5 group but increased the proportion in the L4 group. Conclusions Painful SNL nerve injury depresses resting [Ca]c in sensory neurons. This is most marked in axotomized neurons, especially the large and capsaicin-insensitive neurons presumed to transmit non-nociceptive sensory information.

scholarly journals Activation of a nerve injury transcriptional signature in airway-innervating sensory neurons after LPS induced lung inflammation

2019 ◽  
Author(s):  
Melanie Maya Kaelberer ◽  
Ana Isabel Caceres ◽  
Sven-Eric Jordt
Keyword(s):  
Nerve Injury ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Lung Inflammation ◽  
Dorsal Root ◽  
The Other ◽  
Sensory Ganglia ◽  
Functional Changes ◽  
Transcriptional Signature ◽  
Nodose Ganglia

ABSTRACTThe lungs, the immune and nervous systems functionally interact to respond to respiratory environmental exposures and infections. The lungs are innervated by vagal sensory neurons of the jugular and nodose ganglia, fused together in smaller mammals as the jugular-nodose complex (JNC). While the JNC shares properties with the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG), these sensory structures express differential sets of genes that reflect their unique functionalities. Here, we used RNAseq in mice to identify the differential transcriptomes of the three sensory ganglia types. Using a fluorescent retrograde tracer and fluorescence-activated cell sorting we isolated a defined population of airway-innervating JNC neurons and determined their differential transcriptional map after pulmonary exposure to lipopolysaccharide (LPS), a major mediator of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after infection with Gram-negative bacteria or inhalation of organic dust. JNC neurons activated an injury response program leading to increased expression of gene products such as the G-protein coupled receptors, Cckbr, inducing functional changes in neuronal sensitivity to peptides, and Gpr151, also rapidly induced upon neuropathic nerve injury in pain models. Unique JNC-specific transcripts, present at only minimal levels in TG, DRG and other organs, were identified. These included TMC3, encoding for a putative mechanosensor, and Urotensin 2B, a hypertensive peptide. These findings highlight the unique properties of the JNC and reveal that ALI/ARDS rapidly induce a nerve-injury related state changing vagal excitability.SIGNIFICANCE STATEMENTThe lungs are innervated by sensory neurons of the jugular-nodose ganglia complex (JNC) that detect toxic exposures and interact with lung-resident cells and the immune system to respond to pathogens and inflammation. Here we report the expression of specific genes that differentiate these neurons from neurons in the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG). Through nerve tracing we identified and isolated airway innervating JNC neurons and determined their differential transcriptional map after lung inflammation induced by a bacterial product, lipopolysaccharide (LPS). We observed the rapid activation of a nerve injury transcriptional program that increased nerve sensitivity to inflammation. This mechanism may result in more permanent nerve injury associated with chronic cough and other respiratory complications.

scholarly journals Depletion of Calcium Stores in Injured Sensory Neurons

2009 ◽  
Vol 111 (2) ◽  
pp. 393-405 ◽  
Author(s):  
Geza Gemes ◽  
Marcel Rigaud ◽  
Paul D. Weyker ◽  
Stephen E. Abram ◽  
Dorothee Weihrauch ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Spinal Nerve ◽  
Calcium Stores ◽  
Functional Importance ◽  
Electrophysiological Recordings ◽  
Intracellular Ca ◽  
Functional Consequences

Background Painful nerve injury leads to disrupted Ca signaling in primary sensory neurons, including decreased endoplasmic reticulum (ER) Ca storage. This study examines potential causes and functional consequences of Ca store limitation after injury. Methods Neurons were dissociated from axotomized fifth lumbar (L5) and the adjacent L4 dorsal root ganglia after L5 spinal nerve ligation that produced hyperalgesia, and they were compared to neurons from control animals. Intracellular Ca levels were measured with Fura-2 microfluorometry, and ER was labeled with probes or antibodies. Ultrastructural morphology was analyzed by electron microscopy of nondissociated dorsal root ganglia, and intracellular electrophysiological recordings were obtained from intact ganglia. Results Live neuron staining with BODIPY FL-X thapsigargin (Invitrogen, Carlsbad, CA) revealed a 40% decrease in sarco-endoplasmic reticulum Ca-ATPase binding in axotomized L5 neurons and a 34% decrease in L4 neurons. Immunocytochemical labeling for the ER Ca-binding protein calreticulin was unaffected by injury. Total length of ER profiles in electron micrographs was reduced by 53% in small axotomized L5 neurons, but it was increased in L4 neurons. Cisternal stacks of ER and aggregation of ribosomes occurred less frequently in axotomized neurons. Ca-induced Ca release, examined by microfluorometry with dantrolene, was eliminated in axotomized neurons. Pharmacologic blockade of Ca-induced Ca release with dantrolene produced hyperexcitability in control neurons, confirming its functional importance. Conclusions After axotomy, ER Ca stores are reduced by anatomic loss and possibly diminished sarco-endoplasmic reticulum Ca-ATPase. The resulting disruption of Ca-induced Ca release and protein synthesis may contribute to the generation of neuropathic pain.

An update on the spinal and peripheral pathways of pain signalling

e-Neuroforum ◽  
2017 ◽  
Vol 23 (3) ◽  
Author(s):  
Stefan G. Lechner
Keyword(s):  
Spinal Cord ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Neural Circuits ◽  
Sensory Information ◽  
Brain Regions ◽  
Sensory Afferents ◽  
Different Types ◽  
Functionally Diverse

AbstractPainful or potentially tissue-damaging stimuli are detected by primary sensory afferents that innervate the skin as well as internal tissues. The neurons that give rise to sensory afferents are located in the dorsal root ganglia (DRG) and transmit sensory information to the spinal cord where it is processed and further relayed to higher brain regions to ultimately generate the perception of pain. Both the DRGs as well as the spinal cord comprise a variety of morphologically, molecularly and functionally diverse neurons. The objective of this review is to provide an overview of the different types of sensory neurons and their proposed role in pain signalling. Moreover, I will discuss how pain related sensory information is processed in the dorsal horn of the spinal cord with an emphasis on recently delineated neural circuits that mediate pain hypersensitivity in the setting of nerve injury and inflammation.

scholarly journals 2D vs 3D morphological analysis of dorsal root ganglia in health and painful neuropathy

2021 ◽  
Vol 65 (s1) ◽  
Author(s):  
Valentina Alda Carozzi ◽  
Chiara Salio ◽  
Virginia Rodriguez-Menendez ◽  
Elisa Ciglieri ◽  
Francesco Ferrini
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Sensory Information ◽  
Painful Neuropathy ◽  
Tissue Slices ◽  
Satellite Glial Cells ◽  
Whole Mount ◽  
Functional Features ◽  
Neurochemical Changes

Dorsal root ganglia (DRGs) are clusters of sensory neurons that transmit the sensory information from the periphery to the central nervous system, and satellite glial cells (SGCs), their supporting trophic cells. Sensory neurons are pseudounipolar neurons with a heterogeneous neurochemistry reflecting their functional features. DRGs, not protected by the blood brain barrier, are vulnerable to stress and damage of different origin (i.e., toxic, mechanical, metabolic, genetic) that can involve sensory neurons, SGCs or, considering their intimate intercommunication, both cell populations. DRG damage, primary or secondary to nerve damage, produces a sensory peripheral neuropathy, characterized by neurophysiological abnormalities, numbness, paraesthesia and dysesthesia, tingling and burning sensations and neuropathic pain. DRG stress can be morphologically detected by light and electron microscope analysis with alterations in cell size (swelling/atrophy) and in different sub-cellular compartments (i.e., mitochondria, endoplasmic reticulum, and nucleus) of neurons and/or SGCs. In addition, neurochemical changes can be used to portray abnormalities of neurons and SGC. Conventional immunostaining, i.e., immunohistochemical detection of specific molecules in tissue slices can be employed to detect, localize and quantify particular markers of damage in neurons (i.e., nuclear expression ATF3) or SGCs (i.e., increased expression of GFAP), markers of apoptosis (i.e., caspases), markers of mitochondrial suffering and oxidative stress (i.e., 8-OHdG), markers of tissue inflammation (i.e., CD68 for macrophage infiltration), etc. However classical (2D) methods of immunostaining disrupt the overall organization of the DRG, thus resulting in the loss of some crucial information. Whole-mount (3D) methods have been recently developed to investigate DRG morphology and neurochemistry without tissue slicing, giving the opportunity to study the intimate relationship between SGCs and sensory neurons in health and disease. Here, we aim to compare classical (2D) vs whole-mount (3D) approaches to highlight “pros” and “cons” of the two methodologies when analysing neuropathy-induced alterations in DRGs.

scholarly journals Upregulation of Casein Kinase 1∊ in Dorsal Root Ganglia and Spinal Cord after Mouse Spinal Nerve Injury Contributes to Neuropathic Pain

2009 ◽  
Vol 5 ◽  
pp. 1744-8069-5-74 ◽  
Author(s):  
Eri Sakurai ◽  
Takashi Kurihara ◽  
Kasumi Kouchi ◽  
Hironao Saegusa ◽  
Shuqin Zong ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Spinal Nerve ◽  
Casein Kinase ◽  
Casein Kinase 1

Proteomics study of neuropathic and nonneuropathic dorsal root ganglia: altered protein regulation following segmental spinal nerve ligation injury

2007 ◽  
Vol 29 (2) ◽  
pp. 215-230 ◽  
Author(s):  
Naoka Komori ◽  
Nobuaki Takemori ◽  
Hee Kee Kim ◽  
Anil Singh ◽  
Seon-Hee Hwang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Proteomics Study

Peripheral nerve injury is often followed by the development of severe neuropathic pain. Nerve degeneration accompanied by inflammatory mediators is thought to play a role in generation of neuropathic pain. Neuronal cell death follows axonal degeneration, devastating a vast number of molecules in injured neurons and the neighboring cells. Because we have little understanding of the cellular and molecular mechanisms underlying neuronal cell death triggered by nerve injury, we conducted a proteomics study of rat 4th and 5th lumbar (L4 and L5) dorsal root ganglion (DRG) after L5 spinal nerve ligation. DRG proteins were displayed on two-dimensional gels and analyzed through quantitative densitometry, statistical validation of the quantitative data, and peptide mass fingerprinting for protein identification. Among ≈1,300 protein spots detected on each gel, we discovered 67 proteins that were tightly regulated by nerve ligation. We find that the injury to primary sensory neurons turned on multiple cellular mechanisms critical for the structural and functional integrity of neurons and for the defense against oxidative damage. Our data indicate that the regulation of metabolic enzymes was carefully orchestrated to meet the altered energy requirement of the DRG cells. Our data also demonstrate that ligation of the L5 spinal nerve led to the upregulation in the L4 DRG of the proteins that are highly expressed in embryonic sensory neurons. To understand the molecular mechanisms underlying neuropathic pain, we need to comprehend such dynamic aspect of protein modulations that follow nerve injury.

BDNF-TrkB and proBDNF-p75NTR/Sortilin Signaling Pathways are Involved in Mitochondria-Mediated Neuronal Apoptosis in Dorsal Root Ganglia after Sciatic Nerve Transection

2020 ◽  
Vol 19 (1) ◽  
pp. 66-82 ◽  
Author(s):  
Xianbin Wang ◽  
Wei Ma ◽  
Tongtong Wang ◽  
Jinwei Yang ◽  
Zhen Wu ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
Signaling Pathways ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Neuronal Apoptosis ◽  
Nerve Transection ◽  
Sciatic Nerve Transection

Background: Brain-Derived Neurotrophic Factor (BDNF) plays critical roles during development of the central and peripheral nervous systems, as well as in neuronal survival after injury. Although proBDNF induces neuronal apoptosis after injury in vivo, whether it can also act as a death factor in vitro and in vivo under physiological conditions and after nerve injury, as well as its mechanism of inducing apoptosis, is still unclear. Objective: In this study, we investigated the mechanisms by which proBDNF causes apoptosis in sensory neurons and Satellite Glial Cells (SGCs) in Dorsal Root Ganglia (DRG) After Sciatic Nerve Transection (SNT). Methods: SGCs cultures were prepared and a scratch model was established to analyze the role of proBDNF in sensory neurons and SGCs in DRG following SNT. Following treatment with proBDNF antiserum, TUNEL and immunohistochemistry staining were used to detect the expression of Glial Fibrillary Acidic Protein (GFAP) and Calcitonin Gene-Related Peptide (CGRP) in DRG tissue; immunocytochemistry and Cell Counting Kit-8 (CCK8) assay were used to detect GFAP expression and cell viability of SGCs, respectively. RT-qPCR, western blot, and ELISA were used to measure mRNA and protein levels, respectively, of key factors in BDNF-TrkB, proBDNF-p75NTR/sortilin, and apoptosis signaling pathways. Results: proBDNF induced mitochondrial apoptosis of SGCs and neurons by modulating BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways. In addition, neuroprotection was achieved by inhibiting the biological activity of endogenous proBDNF protein by injection of anti-proBDNF serum. Furthermore, the anti-proBDNF serum inhibited the activation of SGCs and promoted their proliferation. Conclusion: proBDNF induced apoptosis in SGCs and sensory neurons in DRG following SNT. The proBDNF signaling pathway is a potential novel therapeutic target for reducing sensory neuron and SGCs loss following peripheral nerve injury.

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