scholarly journals Trigeminal Nociceptors Express TLR-4 and CD14: a Mechanism for Pain due to Infection

2006 ◽  
Vol 85 (1) ◽  
pp. 49-53 ◽  
Author(s):  
R. Wadachi ◽  
K.M. Hargreaves
Keyword(s):  
Sensory Neurons ◽  
Bacterial Infections ◽  
Bacterial Species ◽  
Nociceptive Neurons ◽  
Odontogenic Infections ◽  
Trigeminal Neurons ◽  
Human Dental Pulp ◽  
Peripheral Sensory ◽  
Caries Lesions ◽  
Immunohistochemical Analyses

Although certain bacterial species appear to be risk factors for pain due to odontogenic infections, comparatively little is known about the potential mechanisms mediating this effect. In this study, we tested the hypothesis that trigeminal nociceptive neurons express the TLR4 or CD14 receptors, thus enabling sensory neurons to detect and respond to tissue levels of bacterial substances such as lipopolysaccharide (LPS). Immunohistochemical analyses of human and rat trigeminal neurons demonstrated that a capsaicin-sensitive subclass of nociceptors (defined by expression of TRPV1, a capsaicin receptor) expresses both TLR4 and CD14. Moreover, human dental pulp collected from patients with caries lesions demonstrated co-localization of TLR4 and CD14, with markers of peripheral sensory neurons. Collectively, these studies indicate that the capsaicin-sensitive subclass of trigeminal nociceptors expresses TLR4 and CD14. These results indicate that pain due to bacterial infections may result, in part, from direct activation of nociceptors by bacterial products such as LPS.

scholarly journals Selective Expression of a SNARE-Cleaving Protease in Peripheral Sensory Neurons Attenuates Pain-Related Gene Transcription and Neuropeptide Release

2021 ◽  
Vol 22 (16) ◽  
pp. 8826
Author(s):  
Wanzhi Wang ◽  
Miaomiao Kong ◽  
Yu Dou ◽  
Shanghai Xue ◽  
Yang Liu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Safety Concern ◽  
Unmet Need ◽  
Nociceptive Neurons ◽  
Neuropeptide Release ◽  
Selective Expression ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1; CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A; NPY2R, neuropeptide Y receptor Y2; GPR52, G protein-coupled receptor 52; SCN9A, sodium voltage-gated channel alpha subunit 9; TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.

scholarly journals Aldosterone Synthase in Peripheral Sensory Neurons Contributes to Mechanical Hypersensitivity during Local Inflammation in Rats

2020 ◽  
Vol 132 (4) ◽  
pp. 867-880 ◽  
Author(s):  
Doaa M. Mohamed ◽  
Mohammed Shaqura ◽  
Xiongjuan Li ◽  
Mehdi Shakibaei ◽  
Antje Beyer ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Mineralocorticoid Receptor ◽  
Mineralocorticoid Receptors ◽  
Mineralocorticoid Receptor Antagonist ◽  
Aldosterone Synthase ◽  
Nociceptive Neurons ◽  
Processing Enzyme ◽  
Peripheral Sensory Neurons ◽  
Synthase Inhibitor ◽  
Peripheral Sensory

Abstract Background Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. Methods In male Wistar rats (n = 5 to 8 per group) with Freund’s complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase–polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. Results In rats with Freund’s complete adjuvant–induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). Conclusions Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Integrins protect sensory neurons in models of paclitaxel-induced peripheral sensory neuropathy

2021 ◽  
Vol 118 (15) ◽  
pp. e2006050118 ◽  
Author(s):  
Grace Ji-eun Shin ◽  
Maria Elena Pero ◽  
Luke A. Hammond ◽  
Anita Burgos ◽  
Atul Kumar ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Therapeutic Potential ◽  
Sensory Neuropathy ◽  
Nociceptive Neuron ◽  
Cellular Mechanisms ◽  
Recycling Endosomes ◽  
Nociceptive Neurons ◽  
Nociceptive Responses ◽  
Peripheral Sensory ◽  
Paclitaxel Treatment

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.

scholarly journals Integrins protect nociceptive neurons in models of paclitaxel-mediated peripheral sensory neuropathy

2019 ◽  
Author(s):  
Grace Ji-eun Shin ◽  
Maria Elena Pero ◽  
Luke A. Hammond ◽  
Anita Burgos ◽  
Samantha E. Galindo ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Therapeutic Potential ◽  
Sensory Neuropathy ◽  
Cellular Mechanisms ◽  
Nociceptive Neurons ◽  
Nociceptive Responses ◽  
High Prevalence ◽  
Neuronal Maintenance ◽  
Peripheral Sensory ◽  
Paclitaxel Treatment

SummaryChemotherapy induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN primarily affects unmyelinated nociceptive sensory terminals. Despite the high prevalence of CIPN, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused sensory neuron degeneration, altered the terminal branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-mediated cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. We used primary dorsal root ganglia neuron cultures to test conservation of integrin-mediated protection. We show that overexpression of a human integrin β subunit 1 (ITGB1) also prevented degeneration following paclitaxel treatment. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring integrin levels to antagonize paclitaxel-mediated toxicity in sensory neurons.

Effects of CGRP-Primed Dental Pulp Stem Cells on Trigeminal Sensory Neurons

2021 ◽  
pp. 002203452110048
Author(s):  
B. Michot ◽  
S.M. Casey ◽  
J.L. Gibbs
Keyword(s):  
Stem Cells ◽  
Sensory Neurons ◽  
Dental Pulp ◽  
Quantitative Polymerase Chain Reaction ◽  
Primary Cultures ◽  
Dental Pulp Stem Cells ◽  
Afferent Activity ◽  
Cytokines And Chemokines ◽  
Trigeminal Neurons ◽  
Trigeminal Neuron

Dental pulp stem cells (DPSCs) are important in tooth physiology, contributing to development, repair, regeneration, and immunomodulatory processes. However, their role in inflammatory mechanisms underlying pulpitis is not well understood. We evaluated the influence of DPSCs stimulated with calcitonin gene-related peptide (CGRP), a proinflammatory neuropeptide, on the expression of mediators released from DPSCs and the effect of these mediators on sensory neuron activity. Human DPSCs were treated with either control media or media containing CGRP (10−8 M) for 7 d, and the conditioned media (CM) containing DPSC-released mediators was collected. The expression of cytokines and chemokines from DPSCs was evaluated by reverse transcription quantitative polymerase chain reaction. The effects of the CM from CGRP-primed DPSCs (primed DPSC-CM) were evaluated on sensory afferents by using primary cultures of mouse trigeminal neurons and an organotypic model of cultured human pulp slices. Mouse trigeminal neurons and human pulp explants were pretreated for 24 h with control or primed DPSC-CM and then stimulated with capsaicin. Afferent activity was measured by quantifying the response to capsaicin via live cell calcium imaging in mouse neurons and CGRP released from pulp explants. Gene expression analysis showed that primed DPSCs overexpressed some proinflammatory cytokines and chemokines, including chemokines CXCL1 and CXCL8, which are both agonists of the receptor CXCR2 expressed in sensory neurons. Primed DPSC-CM increased human pulp sensory afferent activity as compared with control DPSC-CM. Similarly, primed DPSC-CM increased the intensity of calcium responses in cultured mouse trigeminal neurons. Furthermore, the CXCR2 antagonist SB225002 prevented trigeminal neuron sensitization to capsaicin induced by primed DPSC-CM. In conclusion, mediators released by DPSCs, primed with the proinflammatory mediator CGRP, induce neuronal sensitization through CXCR2 receptor. These data suggest that DPSCs might contribute to pain symptoms that develop in pulpitis.

Modulation of μ-opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase γ

Neuroscience ◽  
2010 ◽  
Vol 169 (1) ◽  
pp. 449-454 ◽  
Author(s):  
C. König ◽  
O. Gavrilova-Ruch ◽  
G. Segond von Banchet ◽  
R. Bauer ◽  
M. Grün ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Sensory Neurons ◽  
Receptor Desensitization ◽  
Peripheral Sensory Neurons ◽  
Μ Opioid Receptor ◽  
Phosphoinositide 3 Kinase ◽  
Peripheral Sensory

scholarly journals A-kinase anchoring protein 79/150 coordinates metabotropic glutamate receptor sensitization of peripheral sensory neurons

Pain ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 2364-2372 ◽  
Author(s):  
Kalina Szteyn ◽  
Matthew P. Rowan ◽  
Ruben Gomez ◽  
Junhui Du ◽  
Susan M. Carlton ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Sensory Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Metabotropic Glutamate ◽  
Peripheral Sensory Neurons ◽  
Anchoring Protein ◽  
Peripheral Sensory

M2-Receptor Subtype Does Not Mediate Muscarine-Induced Increases in [Ca2+]i in Nociceptive Neurons of Rat Dorsal Root Ganglia

2000 ◽  
Vol 84 (4) ◽  
pp. 1934-1941 ◽  
Author(s):  
Rainer Haberberger ◽  
Reas Scholz ◽  
Wolfgang Kummer ◽  
Michaela Kress
Keyword(s):  
Receptor Antagonist ◽  
Muscarinic Receptor ◽  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Muscarinic Receptor Subtypes ◽  
Rt Pcr ◽  
Nociceptive Neurons

Multiple muscarinic receptor subtypes are present on sensory neurons that may be involved in the modulation of nociception. In this study we focused on the presence of the muscarinic receptor subtypes, M2 and M3 (M2R, M3R), in adult rat lumbar dorsal root ganglia (DRG) at the functional ([Ca2+]i measurement), transcriptional (RT-PCR), and translational level (immunohistochemistry). After 1 day in culture exposure of dissociated medium-sized neurons (20–35 μm diam) to muscarine was followed by rises in [Ca2+]i in 76% of the neurons. The [Ca2+]i increase was absent after removal of extracellular calcium and did not desensitize after repetitive application of the agonist. This rise in [Ca2+]i may be explained by the expression of M3R, which can induce release of calcium from internal stores via inositoltrisphospate. Indeed the effect was antagonized by the muscarinic receptor antagonist atropine as well as by the M3R antagonist, 4-diphenylacetoxy-N-(2 chloroethyl)-piperidine hydrochloride (4-DAMP). The pharmacological identification of M3R was corroborated by RT-PCR of total RNA and single-cell RT-PCR, which revealed the presence of mRNA for M3R in lumbar DRG and in single sensory neurons. In addition, RT-PCR also revealed the expression of M2R, which did not seem to contribute to the calcium changes since it was not prevented by the M2 receptor antagonist, gallamine. Immunohistochemistry demonstrated the presence of M2R and M3R in medium-sized lumbar DRG neurons that also coexpressed binding sites for the lectin I-B4, a marker for mainly cutaneous nociceptors. The occurrence of muscarinic receptors in putative nociceptive I-B4-positive neurons suggests the involvement of these acetylcholine receptors in the modulation of processing of nociceptive stimuli.

scholarly journals Species, Risk Factors, and Antimicrobial Susceptibility Profiles of Bacterial Isolates from HIV-Infected Patients Suspected to Have Pneumonia in Mekelle Zone, Tigray, Northern Ethiopia

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Gebre Adhanom ◽  
Dawit Gebreegziabiher ◽  
Yemane Weldu ◽  
Araya Gebreyesus Wasihun ◽  
Tadele Araya ◽  
...  
Keyword(s):  
Risk Factors ◽  
Antimicrobial Susceptibility ◽  
Bacterial Pneumonia ◽  
Bacterial Infections ◽  
Bacterial Species ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
P Value ◽  
Northern Ethiopia ◽  
Hiv Patients

Background. Pneumonia is a condition, where bacterial infections are implicated as the most common causes of morbidity and mortality in humans. The actual burden of HIV-infected patients with pneumonia is not well documented in Mekelle region of Ethiopia. This study estimated the prevalence of bacterial pneumonia in HIV patients, antimicrobial susceptibility patterns of pathogens implicated in pneumonia, and associated risk factors in Mekelle zone, Tigray, Northern Ethiopia, during August-December 2016. Methods. Sputum specimens were collected from 252 HIV seropositive individuals with suspected pneumonia. Data on sociodemographics and risk factors were also collected using a structured questionnaire. Blood, Chocolate, and Mac Conkey agar plates (Oxoid, Hampshire, UK) were used to grow the isolates. The isolated colonies were identified based on Gram stain, colony morphology, pigmentation, hemolysis, and biochemical tests. The antimicrobial susceptibility test was performed using the modified Kirby-Bauer disc diffusion method. The analysis was performed using SPSS version 22 and p-value < 0.05 with corresponding 95% confidence interval (CI) was considered statistically significant. Results. Out of the 252 samples, 110 (43.7%) were positive for various bacterial species. The predominant bacterial species were Klebsiella pneumoniae (n=26, 23.6 %) followed by Streptococcus pneumoniae (n=17, 15.5 %), Escherichia coli (n=16, 14.5%), Klebsiella spp. (n=15, 13.6%), Staphylococcus aureus (n=9, 8.2%), Enterobacter spp. (n=7, 6.3%), Pseudomonas aeruginosa (4, n=3.6%), Proteus spp. (n=4, 3.6%), Citrobacter freundii (n=7, 6.3%), Streptococcus pyogenes (3, 2.7%), and Haemophilus influenzae (n=2, 1.8%). Young age (18-29), recent CD4+ count less than 350 cells/mL, alcohol consumption, and HIV WHO stage II showed significant association with the occurrence of bacterial pneumonia. Resistance to penicillin, co-trimoxazole, and tetracycline was observed in 81.8%, 39.8%, and 24.5% of the isolates, respectively. Conclusions. The problem of pneumonia among HIV patients was significant in the study area. The high prevalence of drug-resistant bacteria isolated from the patient’s samples possesses a health risk in immunocompromised HIV patients. There is a need to strengthen and expand culture and susceptibility procedures for the administration of appropriate therapy to improve patients management and care which may aid in decreasing the mortality.

Sign in / Sign up

Export Citation Format

Share Document