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Separate transcriptionally regulated pathways specify distinct classes of sister dendrites in a nociceptive neuron.
O'Brien BMJ, Palumbos SD, Novakovic M, Shang X, Sundararajan L, Miller DM
(2017) Dev Biol 432: 248-257
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, DNA-Binding Proteins, Dendrites, Gene Expression Regulation, LIM-Homeodomain Proteins, Membrane Proteins, Nociceptors, Regulatory Elements, Transcriptional, Sensory Receptor Cells, Transcription Factors, Zinc Fingers
Show Abstract · Added March 26, 2019
The dendritic processes of nociceptive neurons transduce external signals into neurochemical cues that alert the organism to potentially damaging stimuli. The receptive field for each sensory neuron is defined by its dendritic arbor, but the mechanisms that shape dendritic architecture are incompletely understood. Using the model nociceptor, the PVD neuron in C. elegans, we determined that two types of PVD lateral branches project along the dorsal/ventral axis to generate the PVD dendritic arbor: (1) Pioneer dendrites that adhere to the epidermis, and (2) Commissural dendrites that fasciculate with circumferential motor neuron processes. Previous reports have shown that the LIM homeodomain transcription factor MEC-3 is required for all higher order PVD branching and that one of its targets, the claudin-like membrane protein HPO-30, preferentially promotes outgrowth of pioneer branches. Here, we show that another MEC-3 target, the conserved TFIIA-like zinc finger transcription factor EGL-46, adopts the alternative role of specifying commissural dendrites. The known EGL-46 binding partner, the TEAD transcription factor EGL-44, is also required for PVD commissural branch outgrowth. Double mutants of hpo-30 and egl-44 show strong enhancement of the lateral branching defect with decreased numbers of both pioneer and commissural dendrites. Thus, HPO-30/Claudin and EGL-46/EGL-44 function downstream of MEC-3 and in parallel acting pathways to direct outgrowth of two distinct classes of PVD dendritic branches.
Copyright © 2017 Elsevier Inc. All rights reserved.
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MeSH Terms
Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx.
Dadi PK, Vierra NC, Days E, Dickerson MT, Vinson PN, Weaver CD, Jacobson DA
(2017) ACS Chem Neurosci 8: 558-568
MeSH Terms: Action Potentials, Animals, Antibodies, Calcium, Dinoprostone, Electric Stimulation, Fluoxetine, Ganglia, Spinal, HEK293 Cells, Humans, Lectins, Mice, Mice, Inbred C57BL, Mutation, Nociceptors, Potassium Channel Blockers, Potassium Channels, Tandem Pore Domain, Protein Synthesis Inhibitors, Tetracycline
Show Abstract · Added November 13, 2017
The two-pore-domain potassium (K2P) channel TREK-2 serves to modulate plasma membrane potential in dorsal root ganglia c-fiber nociceptors, which tunes electrical excitability and nociception. Thus, TREK-2 channels are considered a potential therapeutic target for treating pain; however, there are currently no selective pharmacological tools for TREK-2 channels. Here we report the identification of the first TREK-2 selective activators using a high-throughput fluorescence-based thallium (Tl) flux screen (HTS). An initial pilot screen with a bioactive lipid library identified 11-deoxy prostaglandin F2α as a potent activator of TREK-2 channels (EC ≈ 0.294 μM), which was utilized to optimize the TREK-2 Tl flux assay (Z' = 0.752). A HTS was then performed with 76 575 structurally diverse small molecules. Many small molecules that selectively activate TREK-2 were discovered. As these molecules were able to activate single TREK-2 channels in excised membrane patches, they are likely direct TREK-2 activators. Furthermore, TREK-2 activators reduced primary dorsal root ganglion (DRG) c-fiber Ca influx. Interestingly, some of the selective TREK-2 activators such as 11-deoxy prostaglandin F2α were found to inhibit the K2P channel TREK-1. Utilizing chimeric channels containing portions of TREK-1 and TREK-2, the region of the TREK channels that allows for either small molecule activation or inhibition was identified. This region lies within the second pore domain containing extracellular loop and is predicted to play an important role in modulating TREK channel activity. Moreover, the selective TREK-2 activators identified in this HTS provide important tools for assessing human TREK-2 channel function and investigating their therapeutic potential for treating chronic pain.
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19 MeSH Terms
Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3.
Comer JD, Pan FC, Willet SG, Haldipur P, Millen KJ, Wright CV, Kaltschmidt JA
(2015) Front Neural Circuits 9: 36
MeSH Terms: Age Factors, Amino Acids, Animals, Axons, Body Patterning, Embryo, Mammalian, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Membrane Proteins, Mice, Mice, Transgenic, Motor Activity, Mutation, Nerve Tissue Proteins, Neural Cell Adhesion Molecule L1, Neural Inhibition, Nociceptors, Signal Transduction, Spinal Cord, Transcription Factors
Show Abstract · Added September 1, 2015
Commissural neurons project across the midline at all levels of the central nervous system (CNS), providing bilateral communication critical for the coordination of motor activity and sensory perception. Midline crossing at the spinal ventral midline has been extensively studied and has revealed that multiple developmental lineages contribute to this commissural neuron population. Ventral midline crossing occurs in a manner dependent on Robo3 regulation of Robo/Slit signaling and the ventral commissure is absent in the spinal cord and hindbrain of Robo3 mutants. Midline crossing in the spinal cord is not limited to the ventral midline, however. While prior anatomical studies provide evidence that commissural axons also cross the midline dorsally, little is known of the genetic and molecular properties of dorsally-crossing neurons or of the mechanisms that regulate dorsal midline crossing. In this study, we describe a commissural neuron population that crosses the spinal dorsal midline during the last quarter of embryogenesis in discrete fiber bundles present throughout the rostrocaudal extent of the spinal cord. Using immunohistochemistry, neurotracing, and mouse genetics, we show that this commissural neuron population includes spinal inhibitory neurons and sensory nociceptors. While the floor plate and roof plate are dispensable for dorsal midline crossing, we show that this population depends on Robo/Slit signaling yet crosses the dorsal midline in a Robo3-independent manner. The dorsally-crossing commissural neuron population we describe suggests a substrate circuitry for pain processing in the dorsal spinal cord.
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20 MeSH Terms
Netrin (UNC-6) mediates dendritic self-avoidance.
Smith CJ, Watson JD, VanHoven MK, Colón-Ramos DA, Miller DM
(2012) Nat Neurosci 15: 731-7
MeSH Terms: Animals, Animals, Genetically Modified, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Adhesion Molecules, Cell Movement, Cloning, Molecular, Dendrites, Hot Temperature, Luminescent Proteins, Membrane Proteins, Microscopy, Confocal, Models, Molecular, Mutation, Nerve Tissue Proteins, Netrins, Nociceptors, Signal Transduction, Time Factors, Time-Lapse Imaging
Show Abstract · Added February 3, 2014
Dendrites from a single neuron may be highly branched but typically do not overlap. Self-avoidance behavior has been shown to depend on cell-specific membrane proteins that trigger mutual repulsion. Here we report the unexpected discovery that a diffusible cue, the axon guidance protein UNC-6 (Netrin), is required for self-avoidance of sister dendrites from the PVD nociceptive neuron in Caenorhabditis elegans. We used time-lapse imaging to show that dendrites fail to withdraw upon mutual contact in the absence of UNC-6 signaling. We propose a model in which the UNC-40 (Deleted in Colorectal Cancer; DCC) receptor captures UNC-6 at the tips of growing dendrites for interaction with UNC-5 on the apposing branch to induce mutual repulsion. UNC-40 also responds to dendritic contact through another pathway that is independent of UNC-6. Our findings offer a new model for how an evolutionarily conserved morphogenic cue and its cognate receptors can pattern a fundamental feature of dendritic architecture.
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20 MeSH Terms
C. elegans multi-dendritic sensory neurons: morphology and function.
Albeg A, Smith CJ, Chatzigeorgiou M, Feitelson DG, Hall DH, Schafer WR, Miller DM, Treinin M
(2011) Mol Cell Neurosci 46: 308-17
MeSH Terms: Animals, Animals, Genetically Modified, Behavior, Animal, Caenorhabditis elegans, Escape Reaction, Mechanoreceptors, Motor Activity, Nociceptors, Physical Stimulation, Sensory Receptor Cells, Touch
Show Abstract · Added February 3, 2014
PVD and FLP sensory neurons envelope the body of the C. elegans adult with a highly branched network of thin sensory processes. Both PVD and FLP neurons are mechanosensors. PVD is known to mediate the response to high threshold mechanical stimuli. Thus PVD and FLP neurons are similar in both morphology and function to mammalian nociceptors. To better understand the function of these neurons we generated strains lacking them. Behavioral analysis shows that PVD and FLP regulate movement under normal growth conditions, as animals lacking these neurons demonstrate higher dwelling behavior. In addition, PVD--whose thin branches project across the body-wall muscles--may have a role in proprioception, as ablation of PVD leads to defective posture. Moreover, movement-dependent calcium transients are seen in PVD, a response that requires MEC-10, a subunit of the mechanosensory DEG/ENaC channel that is also required for maintaining wild-type posture. Hence, PVD senses both noxious and innocuous signals to regulate C. elegans behavior, and thus combines the functions of multiple mammalian somatosensory neurons. Finally, strong mechanical stimulation leads to inhibition of egg-laying, and this response also depends on PVD and FLP neurons. Based on all these results we suggest that noxious signals perceived by PVD and FLP promote an escape behavior consisting of increased speed, reduced pauses and reversals, and inhibition of egg-laying.
Copyright © 2010 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Time-lapse imaging and cell-specific expression profiling reveal dynamic branching and molecular determinants of a multi-dendritic nociceptor in C. elegans.
Smith CJ, Watson JD, Spencer WC, O'Brien T, Cha B, Albeg A, Treinin M, Miller DM
(2010) Dev Biol 345: 18-33
MeSH Terms: Animals, Animals, Genetically Modified, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Dendrites, Gene Expression Profiling, Microscopy, Confocal, Microscopy, Video, Molecular Dynamics Simulation, Neurons, Nociceptors, Oligonucleotide Array Sequence Analysis, RNA Interference, Transcription Factors
Show Abstract · Added February 3, 2014
Nociceptive neurons innervate the skin with complex dendritic arbors that respond to pain-evoking stimuli such as harsh mechanical force or extreme temperatures. Here we describe the structure and development of a model nociceptor, the PVD neuron of C. elegans, and identify transcription factors that control morphogenesis of the PVD dendritic arbor. The two PVD neuron cell bodies occupy positions on either the right (PVDR) or left (PVDL) sides of the animal in posterior-lateral locations. Imaging with a GFP reporter revealed a single axon projecting from the PVD soma to the ventral cord and an elaborate, highly branched arbor of dendritic processes that envelop the animal with a web-like array directly beneath the skin. Dendritic branches emerge in a step-wise fashion during larval development and may use an existing network of peripheral nerve cords as guideposts for key branching decisions. Time-lapse imaging revealed that branching is highly dynamic with active extension and withdrawal and that PVD branch overlap is prevented by a contact-dependent self-avoidance, a mechanism that is also employed by sensory neurons in other organisms. With the goal of identifying genes that regulate dendritic morphogenesis, we used the mRNA-tagging method to produce a gene expression profile of PVD during late larval development. This microarray experiment identified>2,000 genes that are 1.5X elevated relative to all larval cells. The enriched transcripts encode a wide range of proteins with potential roles in PVD function (e.g., DEG/ENaC and Trp channels) or development (e.g., UNC-5 and LIN-17/frizzled receptors). We used RNAi and genetic tests to screen 86 transcription factors from this list and identified eleven genes that specify PVD dendritic structure. These transcription factors appear to control discrete steps in PVD morphogenesis and may either promote or limit PVD branching at specific developmental stages. For example, time-lapse imaging revealed that MEC-3 (LIM homeodomain) is required for branch initiation in early larval development whereas EGL-44 (TEAD domain) prevents ectopic PVD branching in the adult. A comparison of PVD-enriched transcripts to a microarray profile of mammalian nociceptors revealed homologous genes with potentially shared nociceptive functions. We conclude that PVD neurons display striking structural, functional and molecular similarities to nociceptive neurons from more complex organisms and can thus provide a useful model system in which to identify evolutionarily conserved determinants of nociceptor fate.
Copyright 2010 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Specific roles for DEG/ENaC and TRP channels in touch and thermosensation in C. elegans nociceptors.
Chatzigeorgiou M, Yoo S, Watson JD, Lee WH, Spencer WC, Kindt KS, Hwang SW, Miller DM, Treinin M, Driscoll M, Schafer WR
(2010) Nat Neurosci 13: 861-8
MeSH Terms: Animals, Animals, Genetically Modified, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Epithelial Sodium Channels, Mechanotransduction, Cellular, Membrane Proteins, Neurons, Nociceptors, Signal Transduction, Sodium Channels, Thermosensing, Touch, Transient Receptor Potential Channels
Show Abstract · Added February 3, 2014
Polymodal nociceptors detect noxious stimuli, including harsh touch, toxic chemicals and extremes of heat and cold. The molecular mechanisms by which nociceptors are able to sense multiple qualitatively distinct stimuli are not well understood. We found that the C. elegans PVD neurons are mulitidendritic nociceptors that respond to harsh touch and cold temperatures. The harsh touch modality specifically required the DEG/ENaC proteins MEC-10 and DEGT-1, which represent putative components of a harsh touch mechanotransduction complex. In contrast, responses to cold required the TRPA-1 channel and were MEC-10 and DEGT-1 independent. Heterologous expression of C. elegans TRPA-1 conferred cold responsiveness to other C. elegans neurons and to mammalian cells, indicating that TRPA-1 is a cold sensor. Our results suggest that C. elegans nociceptors respond to thermal and mechanical stimuli using distinct sets of molecules and identify DEG/ENaC channels as potential receptors for mechanical pain.
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14 MeSH Terms
Anger management style and endogenous opioid function: is gender a moderator?
Bruehl S, al'Absi M, France CR, France J, Harju A, Burns JW, Chung OY
(2007) J Behav Med 30: 209-19
MeSH Terms: Adult, Anger, Anxiety, Depression, Double-Blind Method, Electric Stimulation, Female, Humans, Male, Naltrexone, Narcotic Antagonists, Nociceptors, Opioid Peptides, Pain Threshold, Sex Factors, Skin, Statistics as Topic
Show Abstract · Added March 5, 2014
This study explored possible gender moderation of previously reported associations between elevated trait anger-out and reduced endogenous opioid analgesia. One hundred forty-five healthy participants underwent acute electrocutaneous pain stimulation after placebo and oral opioid blockade in separate sessions. Blockade effects were derived reflecting changes in pain responses induced by opioid blockade. Hierarchical regressions revealed that elevated anger-out was associated with smaller pain threshold blockade effects (less opioid analgesia) in females, with opposite findings in males (interaction p < .001). Similar marginally significant interactions were noted for blockade effects derived for nociceptive flexion reflex threshold, pain tolerance, and pain ratings (p < .10). Anger-in was also associated negatively with pain threshold blockade effects in females but not males (interaction p < .05). Across genders, elevated anger-in was related to smaller pain tolerance blockade effects (p < .01). Overlap with negative affect did not account for these opioid effects. The anger-in/opioid association was partially due to overlap with anger-out, but the converse was not true. These findings provide additional evidence of an association between trait anger-out and endogenous opioid analgesia, but further suggest that gender may moderate these effects. In contrast to past work, anger-in was related to reduced opioid analgesia, although overlap with anger-out may contribute to this finding.
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17 MeSH Terms
Spinal glial glutamate transporters downregulate in rats with taxol-induced hyperalgesia.
Weng HR, Aravindan N, Cata JP, Chen JH, Shaw AD, Dougherty PM
(2005) Neurosci Lett 386: 18-22
MeSH Terms: Amino Acid Transport System X-AG, Animals, Antineoplastic Agents, Phytogenic, Cell Communication, Disease Models, Animal, Down-Regulation, Excitatory Amino Acid Transporter 1, Excitatory Amino Acid Transporter 2, Glutamate Plasma Membrane Transport Proteins, Glutamic Acid, Hyperalgesia, Male, Neuroglia, Nociceptors, Paclitaxel, Peripheral Nervous System Diseases, Posterior Horn Cells, Presynaptic Terminals, Rats, Rats, Sprague-Dawley, Symporters, Synaptic Transmission
Show Abstract · Added October 20, 2015
Changes in the expression of glial glutamate transporters (GLAST and GLT-1) were examined in the spinal cord of rats with chemotherapy (taxol)-induced mechanical hyperalgesia. Immunohistochemical studies show that the expression of both GLAST and GLT-1 in the L4-L5 spinal dorsal horn is decreased by 24% (P<0.001) and 23% (P<0.001), respectively, in rats with taxol-induced hyperalgesia as compared with those in control rats. These changes were further confirmed using an enzyme-linked immunosorbent assay that confirmed downregulation of GLAST by 36% (P<0.05) and GLT-1 by 18% (P<0.05) in the L4-L5 spinal cord of taxol-treated rats. These data indicate that downregulation of glutamate transporters may contribute to the development of hyperalgesia induced by taxol and suggest that glutamate transporters may be a new target for treatment of pain.
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22 MeSH Terms
Adaptive evolution of MRGX2, a human sensory neuron specific gene involved in nociception.
Yang S, Liu Y, Lin AA, Cavalli-Sforza LL, Zhao Z, Su B
(2005) Gene 352: 30-5
MeSH Terms: Adaptation, Physiological, Alleles, Amino Acid Sequence, Animals, DNA, Evolution, Molecular, Gene Frequency, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Afferent, Nociceptors, Pain, Phylogeny, Polymorphism, Genetic, Primates, Protein Structure, Secondary, Receptors, G-Protein-Coupled, Receptors, Neuropeptide, Sequence Analysis, DNA
Show Abstract · Added March 5, 2014
MRGX2, a G-protein-coupled receptor, is specifically expressed in the sensory neurons of the human peripheral nervous system and involved in nociception. Here, we studied DNA polymorphism patterns and evolution of the MRGX2 gene in world-wide human populations and the representative nonhuman primate species. Our results demonstrated that MRGX2 had undergone adaptive changes in the path of human evolution, which were likely caused by Darwinian positive selection. The patterns of DNA sequence polymorphisms in human populations showed an excess of derived substitutions, which against the expectation of neutral evolution, implying that the adaptive evolution of MRGX2 in humans was a relatively recent event. The reconstructed secondary structure of the human MRGX2 revealed that three of the four human-specific amino acid substitutions were located in the extra-cellular domains. Such critical substitutions may alter the interactions between MRGX2 protein and its ligand, thus, potentially led to adaptive changes of the pain-perception-related nervous system during human evolution.
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20 MeSH Terms