scholarly journals NLRP2 Is Overexpressed in Spinal Astrocytes at the Peak of Mechanical Pain Sensitivity during Complete Freund Adjuvant-Induced Persistent Pain

2021 ◽  
Vol 22 (21) ◽  
pp. 11408
Author(s):  
László Ducza ◽  
Péter Szücs ◽  
Krisztina Hegedűs ◽  
Erzsébet Bakk ◽  
Andrea Gajtkó ◽  
...  
Keyword(s):  
Mechanical Allodynia ◽  
Pain Sensitivity ◽  
Neuronal Excitability ◽  
Interleukin 1 ◽  
Active Form ◽  
Persistent Pain ◽  
Spinal Neurons ◽  
Pain Model ◽  
Significant Attenuation ◽  
Lumbar Spinal

Our earlier findings revealed that interleukin-1 receptor type-1 (IL-1R1) was overexpressed in spinal neurons, and IL-1R1-deficient mice showed significant attenuation of thermal and mechanical allodynia during the course of the Complete Freund adjuvant (CFA)-induced persistent pain model. In the present study, we found that a ligand of IL-1R1, termed interleukin-1β (IL-1β), is also significantly overexpressed at the peak of mechanical pain sensitivity in the CFA-evoked pain model. Analysis of cellular distribution and modeling using IMARIS software showed that in the lumbar spinal dorsal horn, IL-1β is significantly elevated by astrocytic expression. Maturation of IL-1β to its active form is facilitated by the formation of the multiprotein complex called inflammasome; thus, we tested the expression of NOD-like receptor proteins (NLRPs) in astrocytes. At the peak of mechanical allodynia, we found expression of the NLRP2 inflammasome sensor and its significantly elevated co-localization with the GFAP astrocytic marker, while NLRP3 was moderately present and NLRP1 showed total segregation from the astrocytic profiles. Our results indicate that peripheral CFA injection induces NLRP2 inflammasome and IL-1β expression in spinal astrocytes. The release of mature IL-1β can contribute to the maintenance of persistent pain by acting on its neuronally expressed receptor, which can lead to altered neuronal excitability.

Gliosis alters expression and uptake of spinal glial amino acid transporters in a mouse neuropathic pain model

2007 ◽  
Vol 3 (2) ◽  
pp. 141-153 ◽  
Author(s):  
Carlo Cavaliere ◽  
Giovanni Cirillo ◽  
Maria Rosaria Bianco ◽  
Francesco Rossi ◽  
Vito De Novellis ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amino Acid ◽  
High Performance ◽  
Persistent Pain ◽  
Lumbar Spinal Cord ◽  
Amino Acid Transporters ◽  
Pain Model ◽  
Proinflammatory Mediators ◽  
Neuropathic Pain Model ◽  
Lumbar Spinal

AbstractGliosis is strongly implicated in the development and maintenance of persistent pain states following chronic constriction injury of the sciatic nerve. Here we demonstrate that in the dorsal horn of the spinal cord, gliosis is accompanied by changes in glial amino acid transporters examined by immunoblot, immunohistochemistry and RT-PCR. Cytokines, proinflammatory mediators and microglia increase up to postoperative day (pd) 3 before decreasing on pd 7. Then, spinal glial fibrillary acidic protein increases on pd 7, lasting until pd 14 and later. Simultaneously, the expression of glial amino acid transporters for glycine and glutamate (GlyT1 and GLT1) is reduced on pd 7 and pd 14. Consistent with a reduced expression of GlyT1 and GLT1, high performance liquid chromatography reveals a net increase in the concentration of glutamate and glycine on pd 7 and pd 14 in tissue from the lumbar spinal cord of neuropathic mice. In this study we have confirmed that microglial activation precedes astrogliosis. Such a glial cytoskeletal rearrangement correlates with a marked decrease in glycine and glutamate transporters, which might, in turn, be responsible for the increased concentration of these neurotransmitters in the spinal cord. We speculate that these phenomena might contribute, via over-stimulation of NMDA receptors, to the changes in synaptic functioning that are responsible for the maintenance of persistent pain.

Changes in serotonin-induced potentials during spinal cord development

1993 ◽  
Vol 69 (4) ◽  
pp. 1338-1349 ◽  
Author(s):  
L. Ziskind-Conhaim ◽  
B. S. Seebach ◽  
B. X. Gao
Keyword(s):  
Spinal Cord ◽  
Direct Action ◽  
Membrane Resistance ◽  
Ventral Horn ◽  
Repetitive Firing ◽  
Lumbar Spinal Cord ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Spinal Neurons ◽  
Lumbar Spinal

1. Motoneuron responses to serotonin (5-hydroxytryptamine, 5-HT), and the growth pattern of 5-HT projections into the ventral horn were studied in the isolated spinal cord of embryonic and neonatal rats. 2. 5-HT projections first appeared in lumbar spinal cord at days 16-17 of gestation (E16-E17) and were localized in the lateral and ventral funiculi. By E18, the projections had grown into the ventral horn, and at 1-2 days after birth they were in close apposition to motoneuron somata. 3. At E16-E17, slow-rising depolarizing potentials of 1-4 mV were recorded intracellularly in lumbar motoneurons in response to bath application of 5-HT. These potentials were not apparent after E18; at that time 5-HT generated long-lasting depolarizations with an average amplitude of 6 mV, and an increase of 11% in membrane resistance. Starting at E18, 5-HT also induced high-frequency fast-rising potentials that were blocked by antagonists of glutamate, gamma-aminobutyric acid, and glycine. 4. Motoneuron responses to 5-HT increased significantly after birth, when 5-HT produced an average depolarization of 19 mV and repetitive firing of action potentials. 5. Tetrodotoxin and high Mg2+ did not reduce the amplitude of the long-lasting depolarizations, which suggested that they were produced by direct action of 5-HT on motoneuron membrane. 6. At all developmental ages, 5-HT reduced the amplitude of dorsal root-evoked potentials. The suppressed responses were neither due to 5-HT-induced depolarization nor the result of a decrease in motoneuron excitability. 7. The pharmacological profile of 5-HT-induced potentials was studied with the use of various agonists and antagonists of 5-HT. The findings indicated that the actions of 5-HT on spinal neurons were mediated via multiple 5-HT receptor subtypes. 8. Our results suggested that 5-HT excited spinal neurons before 5-HT projections grew into the ventral horn. The characteristics of 5-HT-induced potentials changed, however, at the time when the density of 5-HT projections increased in the motor nuclei.

scholarly journals The Influence of Pain Sensitivity on the Symptom Severity in Patients with Lumbar Spinal Stenosis

2013 ◽  
Vol 2;16 (2;3) ◽  
pp. 135-144
Author(s):  
Jin S. JYeom
Keyword(s):  
Back Pain ◽  
Spinal Stenosis ◽  
Disc Degeneration ◽  
Lumbar Spinal Stenosis ◽  
Pain Sensitivity ◽  
Leg Pain ◽  
Canal Stenosis ◽  
Sf 36 ◽  
The Individual ◽  
Lumbar Spinal

Background: The symptom severity of back pain/leg pain is not correlated with the severity of degenerative changes and canal stenosis in lumbar stenosis. Considering the individual pain sensitivity might play an important role in pain perception, this discordance between the radiologic findings and clinical symptoms in degenerative lumbar stenosis might originate from the individual difference of pain sensitivity for back pain and/or leg pain. Objective: To determine the relationship among the clinical symptoms, radiologic findings, and the individual pain sensitivity in the patients with degenerative lumbar spinal stenosis. Study Design: Retrospective analysis of prospectively collected data. Setting: A spine center in the department of orthopedic surgery. Methods: In 94 patients who had chronic back pain and/or leg pain caused by degenerative lumbar spinal stenosis, a medical history, a physical examination, and completion of a series of questionnaires, including pain sensitivity questionnaire (PSQ) [total PSQ and PSQ-minor], Oswestry Disability Index (ODI), Visual Analog Pain Scale (VAS) for back pain, and Short Form36 (SF-36) were recorded on the first visit. Radiologic analysis was performed using the MRI findings. The grading of canal stenosis was based on the method by Schizas, and the degree of disc degeneration was graded from T2-weighted images with the Pfirrmann classification. The correlations among variables were statistically analyzed. Results: Total PSQ and PSQ-minor were not dependent on the grade of canal stenosis after gender adjustment. VAS for leg pain and back pain was highly associated with the total PSQ and the PSQ-minor. Total PSQ and PSQ-minor were also significantly associated with ODI. Among SF36 scales, the PSQ minor had significant correlations with SF-36 such as bodily pain (BP), Roleemotional (RE), and Mental Component Summary (MCS) after control of confounding variables such as body mass index (BMI), age, and the grade of canal stenosis/disc degeneration. Total PSQ was significantly associated with the SF-36 RP, BP, and RE. Furthermore, after adjustment for gender and pain sensitivity, there was no significant association between the grade of canal stenosis and VAS for back pain/leg pain and ODI, and no correlation was found between the grade of disc degeneration and VAS for back pain/leg pain and ODI, either. Limitations: The multiple lesions of canal stenosis and/or disc degeneration and the grade of facet degeneration were not considered as a variable. Conclusion: The current study suggests that the pain sensitivity could be a determining factor for symptom severity in the degenerative spinal disease. Key words: Pain sensitivity, pain sensitivity questionnaire, lumbar spinal stenosis, visual analog pain scale, Oswestry disability index, Short Form-36

Features of laminar and somatotopic organization of lumbar spinal cord units receiving cutaneous inputs from hindlimb receptive fields

1984 ◽  
Vol 52 (3) ◽  
pp. 449-458 ◽  
Author(s):  
A. R. Light ◽  
R. G. Durkovic
Keyword(s):  
Spinal Cord ◽  
Receptive Field ◽  
Receptive Fields ◽  
Lumbar Spinal Cord ◽  
Spinal Neurons ◽  
Spinal Cord Neurons ◽  
Somatotopic Organization ◽  
Single Unit Recordings ◽  
Lumbar Spinal ◽  
Rectangular Columns

Single-unit recordings from 312 units of lamina I-VII of the lumbar spinal cord of unanesthetized, decerebrate, T8 spinal cats were used to determine the somatotopic and laminar organization of spinal neurons responding to cutaneous stimulation of the hindlimb. Properties of cells confined to different Rexed laminae (I-VII) were shown to differ in several respects, including responses to variations in stimulus intensity, receptive-field areas, spontaneous frequencies, and central delays. Spinal cord neurons with similarly localized cutaneous receptive fields were found to be organized in sagittally oriented rectangular columns. These columns were 7 to at least 20 mm long (rostral-caudal axis), 0.5-1.0 mm wide, and could encompass laminae I-VII in depth. Touch, pressure, and pinch were effective excitatory inputs into each column subserving a given receptive-field location. A map of the somatotopic organization of units in the horizontal plane is presented, which in general confirms previous reports and in particular deals with the organization of units with receptive fields on the plantar cushion and individual toes.

scholarly journals Lysosomal cysteine endopeptidases mediate interleukin 1-stimulated cartilage proteoglycan degradation

1992 ◽  
Vol 287 (2) ◽  
pp. 657-661 ◽  
Author(s):  
D J Buttle ◽  
J Saklatvala
Keyword(s):  
Interleukin 1 ◽  
Active Form ◽  
Growth Factor Receptor ◽  
Test System ◽  
Significant Inhibition ◽  
Cartilage Explants ◽  
Cartilage Proteoglycan ◽  
Proteoglycan Degradation ◽  
Cysteine Endopeptidases ◽  
Proteoglycan Release

The peptidyl diazomethane inactivator of cysteine endopeptidases, benzyloxycarbonyl-Tyr-Ala-CHN2, was tested as an inhibitor of interleukin 1 alpha-stimulated release of proteoglycan from bovine nasal septum cartilage explants. Like the previously tested epoxidyl peptide proinhibitor trans-epoxysuccinyl-leucylamido-(3-methyl)butane ethyl ester, it proved to be an effective inhibitor of proteoglycan release from cartilage, with significant inhibition at a concentration of 1 microM. The inhibition did not seem to be due to a general toxic effect. The rates of inactivation of the bovine cysteine endopeptidases by the peptidyl diazomethane, the epoxidyl peptide proinhibitor and its active form were determined. Benzyloxycarbonyl-Tyr-Ala-CHN2 proved to be a rapid inactivator of cathepsins L, S and B, but reacted much more slowly with cathepsin H and calpain. Thus it would appear that the latter two enzymes are not implicated in proteoglycan release in our test system. The peptidyl diazomethane and epoxidyl peptide proinhibitor (above) were also tested for their effects on three other interleukin 1-mediated cellular events, namely epidermal growth factor receptor transmodulation, and interleukin 6 and prostaglandin E2 production. In all cases the inactivators did not interfere with the response to interleukin 1 in human gingival fibroblasts. We conclude that one or more of the lysosomal cysteine endopeptidases cathepsins B, L and S mediate interleukin 1-stimulated cartilage proteoglycan degradation without affecting signal transduction.

Brain-derived neurotrophic factor stimulation of T-type Ca2+ channels in sensory neurons contributes to increased peripheral pain sensitivity

2019 ◽  
Vol 12 (600) ◽  
pp. eaaw2300 ◽  
Author(s):  
Hua Wang ◽  
Yuan Wei ◽  
Yichen Pu ◽  
Dongsheng Jiang ◽  
Xinghong Jiang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Sensory Neurons ◽  
Neurotrophic Factor ◽  
Pain Sensitivity ◽  
Neuronal Excitability ◽  
Brain Derived Neurotrophic Factor ◽  
Mitogen Activated Protein Kinase ◽  
Mechanical Stimuli ◽  
Action Potential Firing ◽  
Stimulation Of

Although brain-derived neurotrophic factor (BDNF) is implicated in the nociceptive signaling of peripheral sensory neurons, the underlying mechanisms remain largely unknown. Here, we elucidated the effects of BDNF on the neuronal excitability of trigeminal ganglion (TG) neurons and the pain sensitivity of rats mediated by T-type Ca2+ channels. BDNF reversibly and dose-dependently enhanced T-type channel currents through the activation of tropomyosin receptor kinase B (TrkB). Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its downstream target, the kinase AKT, abolished the BDNF-induced T-type channel response. BDNF application activated p38 mitogen-activated protein kinase (MAPK), and this effect was prevented by inhibition of PI3K but not of protein kinase A (PKA). Antagonism of either PI3K or p38 MAPK prevented the BDNF-induced stimulation of PKA activity, whereas PKA inhibition blocked the BDNF-mediated increase in T-type currents. BDNF increased the rate of action potential firing in TG neurons and enhanced the pain sensitivity of rats to mechanical stimuli. Moreover, inhibition of TrkB signaling abolished the increased mechanical sensitivity in a rat model of chronic inflammatory pain, and this effect was attenuated by either T-type channel blockade or knockdown of the channel Cav3.2. Together, our findings indicate that BDNF enhances T-type currents through the stimulation of TrkB coupled to PI3K-p38-PKA signaling, thereby inducing neuronal hyperexcitability of TG neurons and pain hypersensitivity in rats.

scholarly journals The Anti-Tumor Agent Sodium Selenate Decreases Methylated PP2A, Increases GSK3βY216 Phosphorylation, Including Tau Disease Epitopes and Reduces Neuronal Excitability in SHSY-5Y Neurons

2019 ◽  
Vol 20 (4) ◽  
pp. 844 ◽  
Author(s):  
Wesal Habbab ◽  
Imad Aoudé ◽  
Freshteh Palangi ◽  
Sara Abdulla ◽  
Tariq Ahmed
Keyword(s):  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Active Form ◽  
Close Correlation ◽  
Maximum Effect ◽  
Sodium Selenate ◽  
Dependent Manner ◽  
Maximum Increase ◽  
Electrophysiological Studies ◽  
Catalytically Active

Selenium application as sodium selenate was repeatedly shown to have anti-carcinogenic properties by increasing levels of the serine/ threonine protein phosphatase 2A (PP2A) in cancer cells. PP2A has a prominent role in cell development, homeostasis, and in neurons regulates excitability. PP2A, GSK3β and Tau reside together in a complex, which facilitates their interaction and (dys)-function as has been reported for several neurological disorders. In this study we recorded maximum increase in total PP2A at 3 µM sodium selenate in a neuron cell line. In conjunction with these data, whole-cell electrophysiological studies revealed that this concentration had maximum effect on membrane potentials, conductance and currents. Somewhat surprisingly, the catalytically active form, methylated PP2A (mePP2A) was significantly decreased. In close correlation to these data, the phosphorylation state of two substrate proteins, sensitive to PP2A activity, GSK3β and Tau were found to be increased. In summary, our data reveal that sodium selenate enhances PP2A levels, but reduces catalytic activity of PP2A in a dose dependent manner, which fails to reduce Tau and GSK3β phosphorylation under physiological conditions, indicating an alternative route in the rescue of cell pathology in neurological disorders.

scholarly journals Effects of Topical Application of Clonidine Cream on Pain Behaviors and Spinal Fos Protein Expression in Rat Models of Neuropathic Pain, Postoperative Pain, and Inflammatory Pain

2007 ◽  
Vol 107 (3) ◽  
pp. 486-494 ◽  
Author(s):  
Chi Li ◽  
Hiroshi Sekiyama ◽  
Masakazu Hayashida ◽  
Kenji Takeda ◽  
Toshinobu Sumida ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Postoperative Pain ◽  
Topical Application ◽  
Inflammatory Pain ◽  
Mechanical Allodynia ◽  
Thermal Hyperalgesia ◽  
Rat Models ◽  
Pain Behaviors ◽  
Plantar Surface ◽  
Lumbar Spinal

Background Clonidine can effectively reduce pain and/or hypersensitivity. However, the antihypersensitivity effects of clonidine topically applied in cream (CC) have not been investigated. The authors evaluated effects of topical application of CC on pain behaviors and spinal Fos-like immunoreactivity in rats with hypersensitivity. Methods Clonidine (30, 100, and 300 microg/g) was prepared in a cream base. In rat models of neuropathic pain, inflammatory pain, and postoperative pain, the authors evaluated effects of CC (0.1 g), topically applied onto the plantar surface of the injured or uninjured paw, on thermal hyperalgesia and mechanical allodynia to von Frey filaments. The authors also evaluated effects of CC on lumbar spinal Fos-like immunoreactivity. Results In neuropathic rats, CC applied onto the injured paw reduced thermal hyperalgesia and mechanical allodynia dose dependently, whereas CC applied onto the uninjured paw had no effect. The antihypersensitivity effects of CC were antagonized by intraperitoneal yohimbine (10 mg/kg). Further, CC reduced Fos-like immunoreactivity in neuropathic rats. In contrast, CC in a single dose had no effects on hyperalgesia, allodynia, or Fos-like immunoreactivity in rats with inflammatory or postoperative pain. In rats with postoperative pain, CC repeatedly applied for 6 days reduced thermal hyperalgesia, but not mechanical allodynia, in the postoperative days, whereas it had no effects on hyperalgesia or allodynia in those with inflammatory pain. Conclusions Topical CC in concentrations examined significantly reduced hypersensitivity and lumbar spinal Fos-like immunoreactivity in rats with neuropathic pain, probably through activation of peripherally located alpha2 adrenoceptors. However, CC was only partially effective and totally ineffective in rats with postoperative pain and inflammatory pain, respectively.

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