Receptor Subtype Mediating the Adrenergic Sensitivity of Pain Behavior and Ectopic Discharges in Neuropathic Lewis Rats

1999 ◽  
Vol 81 (5) ◽  
pp. 2226-2233 ◽  
Author(s):  
Doo Hyun Lee ◽  
Xianzeng Liu ◽  
Hyun Taek Kim ◽  
Kyungsoon Chung ◽  
Jin Mo Chung
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Pain Behavior ◽  
Receptor Subtype ◽  
Systemic Injection ◽  
Lewis Rats ◽  
Ectopic Discharges

Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. We attempted to identify the subtype of α-adrenergic receptor (α-AR) that is responsible for the sympathetic (adrenergic) dependency of neuropathic pain in the segmental spinal injury (SSI) model in the Lewis strain of rat. This model was chosen because our previous study showed that pain behaviors in this condition are particularly sensitive to systemic injection of phentolamine (PTL), a general α-AR blocker. We examined the effects of specific α1- and α2-AR blockers on 1) behavioral signs of mechanical allodynia, 2) ectopic discharges recorded in the in vivo condition, and 3) ectopic discharges recorded in an in vitro setup. One week after tight ligation of the L5 and L6 spinal nerves, mechanical thresholds of the paw for foot withdrawals were drastically lowered; we interpreted this change as a sign of mechanical allodynia. Signs of mechanical allodynia were significantly relieved by a systemic injection of PTL (a mixed α1- and α2-AR antagonist) or terazosin (TRZ, an α1-AR antagonist) but not by various α2-AR antagonists (idazoxan, rauwolscine, or yohimbine), suggesting that the α1-AR is in part the mediator of the signs of mechanical allodynia. Ongoing ectopic discharges were recorded from injured afferents in fascicles of the L5 dorsal root of the neuropathic rat with an in vivo recording setup. Ongoing discharge rate was significantly reduced after intraperitoneal injection of PTL or TRZ but not by idazoxan. In addition, by using an in vitro recording setup, spontaneous activity was recorded from teased dorsal root fibers in a segment in which the spinal nerve was previously ligated. Application of epinephrine to the perfusion bath enhanced ongoing discharges. This evoked activity was blocked by pretreatment with TRZ but not with idazoxan. This study demonstrated that both behavioral signs of mechanical allodynia and ectopic discharges of injured afferents in the Lewis neuropathic rat are in part mediated by mechanisms involving α1-ARs. These results suggest that the sympathetic dependency of neuropathic pain in the Lewis strain of the rat is mediated by the α1 subtype of AR.

scholarly journals The fibroblast-derived protein PI16 controls neuropathic pain

2020 ◽  
Vol 117 (10) ◽  
pp. 5463-5471 ◽  
Author(s):  
Pooja Singhmar ◽  
Ronnie The Phong Trinh ◽  
Jiacheng Ma ◽  
XiaoJiao Huo ◽  
Bo Peng ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root ◽  
Clinical Problem ◽  
Endothelial Barrier ◽  
Leukocyte Infiltration ◽  
Spared Nerve Injury ◽  
Protein Levels ◽  
Major Clinical Problem

Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here, we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury (SNI) model of neuropathic pain increases PI16 protein levels in fibroblasts in dorsal root ganglia (DRG) meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG, and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes transendothelial leukocyte migration. In vivo, Pi16−/− mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK, and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross-talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx, and increased pain. Its key role in neuropathic pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.

scholarly journals Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Yu-Juan Qu ◽  
Xiao Zhang ◽  
Zhen-Zhen Fan ◽  
Juan Huai ◽  
Yong-Bo Teng ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Mapk Pathway ◽  
Intrathecal Injection ◽  
Ruthenium Red ◽  
Protein Expressions ◽  
Intermediary Role ◽  
Ectopic Discharges

The aim of this study was to investigate the relationships among TRPV4, p38, and neuropathic pain in a rat model of chronic compression of the dorsal root ganglion. Mechanical allodynia appeared after CCD surgery, enhanced via the intrathecal injection of 4α-phorbol 12,13-didecanoate (4α-PDD, an agonist of TRPV4) and anisomycin (an agonist of p38), but was suppressed by Ruthenium Red (RR, an inhibitor of TRPV4) and SB203580 (an inhibitor of p38). The protein expressions of p38 and P-p38 were upregulated by 4α-PDD and anisomycin injection but reduced by RR and SB203580. Moreover, TRPV4 was upregulated by 4α-PDD and SB203580 and downregulated by RR and anisomycin. In DRG tissues, the numbers of TRPV4- or p38-positive small neurons were significantly changed in CCD rats, increased by the agonists, and decreased by the inhibitors. The amplitudes of ectopic discharges were increased by 4α-PDD and anisomycin but decreased by RR and SB203580. Collectively, these results support the link between TRPV4 and p38 and their intermediary role for neuropathic pain in rats with chronic compression of the dorsal root ganglion.

5-HT1A receptor-mediated attenuation of heat hyperalgesia and mechanical allodynia by chrysin in mice with experimental mononeuropathy

2020 ◽  
Vol 45 (8) ◽  
pp. 610-619
Author(s):  
Jiayi Wu ◽  
Yangui Wang ◽  
Wugeng Cui ◽  
Wenhua Zhou ◽  
Xin Zhao
Keyword(s):  
Neuropathic Pain ◽  
Pain Relief ◽  
Monoamine Oxidase ◽  
Mechanical Allodynia ◽  
Hypertensive Crisis ◽  
Maximum Effect ◽  
Repeated Treatment ◽  
Heat Hyperalgesia

BackgroundPersistent neuropathic pain poses a health problem, for which effective therapy or antidote is in dire need. This work aimed to investigate the pain-relieving effect of chrysin, a natural flavonoid with monoamine oxidase inhibitory activity, in an experimental model of neuropathic pain and elucidate mechanism(s).MethodsChronic constriction injury (CCI) was produced by loose ligation of sciatic nerve in mice. The pain-related behaviors were examined using von Frey test and Hargreaves test. The serotonin-related mechanisms were investigated by serotonin depletion with p-chlorophenylalanine (PCPA) and antagonist tests in vivo and in vitro.ResultsRepeated treatment of CCI mice with chrysin (orally, two times per day for 2 weeks) ameliorated heat hyperalgesia and mechanical allodynia in a dose-dependent fashion (3–30 mg/kg). The chrysin-triggered pain relief seems serotonergically dependent, since its antihyperalgesic and antiallodynic actions were abolished by chemical depletion of serotonin by PCPA, whereas potentiated by 5-hydroxytryptophan (a precursor of 5-HT). Consistently, chrysin-treated neuropathic mice showed enhanced levels of spinal monoamines especially 5-HT, with depressed monoamine oxidase activity. Moreover, chrysin-evoked pain relief was preferentially counteracted by 5-HT1A receptor antagonist WAY-100635 delivered systematically or spinally. In vitro, chrysin (0.1–10 nM) increased the maximum effect (Emax, shown as stimulation of [35S] GTPγS binding) of 8-OH-DPAT, a 5-HT1A agonist. Beneficially, chrysin was able to correct comorbid behavioral symptoms of depression and anxiety evoked by neuropathic pain, without causing hypertensive crisis (known as ‘cheese reaction’).ConclusionThese findings confirm the antihyperalgesic and antiallodynic efficacies of chrysin, with spinal 5-HT1A receptors being critically engaged.

scholarly journals Thiamine Suppresses Thermal Hyperalgesia, Inhibits Hyperexcitability, and Lessens Alterations of Sodium Currents in Injured, Dorsal Root Ganglion Neurons in Rats

2009 ◽  
Vol 110 (2) ◽  
pp. 387-400 ◽  
Author(s):  
Xue-Song Song ◽  
Zhi-Jiang Huang ◽  
Xue-Jun Song
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Nerve Injury ◽  
Dorsal Root ◽  
Thermal Hyperalgesia ◽  
B Vitamins ◽  
Drg Neurons ◽  
Na Currents

Background B vitamins can effectively attenuate inflammatory and neuropathic pain in experimental animals, while their efficacy in treating clinical pain syndromes remains unclear. To understand possible mechanisms underlying B vitamin-induced analgesia and provide further evidence that may support the clinical utility of B vitamins in chronic pain treatment, this study investigated effects of thiamine (B1) on the excitability and Na currents of dorsal root ganglion (DRG) neurons that have been altered by nerve injury. Methods Nerve injury was mimicked by chronic compression of DRG in rats. Neuropathic pain was evidenced by the presence of thermal hyperalgesia. Intracellular and patch-clamp recordings were made in vitro from intact and dissociated DRG neurons, respectively. Results (1) In vivo intraperitoneal administration of B1 (66 mg/kg/day, 10-14 doses) significantly inhibited DRG compression-induced neural hyperexcitability, in addition to suppressing thermal hyperalgesia. (2) In vitro perfusion of B1 (0.1, 1 and 10 mM) resulted in a dose-dependent inhibition of DRG neuron hyperexcitability. In addition, the DRG neurons exhibited size-dependent sensitivity to B1 treatment, i.e., the small and the medium-sized neurons, compared to the large neurons, were significantly more sensitive. (3) Both in vitro (1 mM) and in vivo application of B1 significantly reversed DRG compression-induced down-regulation of tetrodotoxin-resistant but not tetrodotoxin-sensitive Na current density in the small neurons. B1 at 1 mM also reversed the compression-induced hyperpolarizing shift of the inactivation curve of the tetrodotoxin-resistant currents and the upregulated ramp currents in small DRG neurons. Conclusion Thiamine can reduce hyperexcitability and lessen alterations of Na currents in injured DRG neurons, in addition to suppressing thermal hyperalgesia.

scholarly journals Upregulation of EMMPRIN (OX47) in Rat Dorsal Root Ganglion Contributes to the Development of Mechanical Allodynia after Nerve Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Qun Wang ◽  
Yanyuan Sun ◽  
Yingna Ren ◽  
Yandong Gao ◽  
Li Tian ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Nerve Injury ◽  
Messenger Rna ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Cellular Localization ◽  
Altered Expression

Matrix metalloproteinases (MMPs) are widely implicated in inflammation and tissue remodeling associated with various neurodegenerative diseases and play an important role in nociception and allodynia. Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) plays a key regulatory role for MMP activities. However, the role of EMMPRIN in the development of neuropathic pain is not clear. Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunofluorescence were performed to determine the changes of messenger RNA and protein of EMMPRIN/OX47 and their cellular localization in the rat dorsal root ganglion (DRG) after nerve injury. Paw withdrawal threshold test was examined to evaluate the pain behavior in spinal nerve ligation (SNL) model. The lentivirus containing OX47 shRNA was injected into the DRG one day before SNL. The expression level of both mRNA and protein of OX47 was markedly upregulated in ipsilateral DRG after SNL. OX47 was mainly expressed in the extracellular matrix of DRG. Administration of shRNA targeted against OX47 in vivo remarkably attenuated mechanical allodynia induced by SNL. In conclusion, peripheral nerve injury induced upregulation of OX47 in the extracellular matrix of DRG. RNA interference against OX47 significantly suppressed the expression of OX47 mRNA and the development of mechanical allodynia. The altered expression of OX47 may contribute to the development of neuropathic pain after nerve injury.

Direct and indirect pharmacological modulation of CCL2/CCR2 pathway results in attenuation of neuropathic pain — In vivo and in vitro evidence

2016 ◽  
Vol 297 ◽  
pp. 9-19 ◽  
Author(s):  
Anna Piotrowska ◽  
Klaudia Kwiatkowski ◽  
Ewelina Rojewska ◽  
Joanna Slusarczyk ◽  
Wioletta Makuch ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Pharmacological Modulation

scholarly journals P11.22 Radiotherapy effects in GBM Rat model CNS1

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii47-iii47
Author(s):  
O Furman ◽  
D Daniels ◽  
D Guez ◽  
D Last ◽  
S Sharabi ◽  
...  
Keyword(s):  
Rat Model ◽  
Tumor Size ◽  
Growth Arrest ◽  
Control Group ◽  
Lewis Rats ◽  
Post Irradiation ◽  
Initial Tumor ◽  
Initial Tumor Size

Abstract BACKGROUND CNS1 is a syngeneic glioma model in Lewis Rats. It is an aggressive infiltrating tumor cell line that mimics important aspects of human GBM such as rapid growth, dispersal along blood vessels and white matter, pseudopallisading cells with features of hemorrhage and necrosis. CNS1 tumors are infiltrated with macrophages and T-cells, and were studied in the context of immunotherapy and gene therapy, extracellular matrix and invasion, but CNS1 response to radiation has not yet been described. If we wish to combine novel immune-based therapies with existing GBM protocols that include radiation and chemotherapy, we will need models that respond to these protocols. As a first step in this direction, we sought to describe CNS1 response to radiation in vitro and in vivo. MATERIAL AND METHODS In vitro, survival of irradiated CNS1 cells was assessed with clonogenic assay. Radiation varied in dose from 0 to 10 Gy and was delivered via Kimtron Polaris X-ray generator. In vivo, male Lewis rats were intra-cranially inoculated with 0.5*106 CNS1 tumor cells and monitored for survival. Treated rats (N=6) were subjected to a single 20Gy whole-head radiation treatment under full anesthesia, delivered five days post-inoculation. Control rats (N=5) were anesthetized but not irradiated. Tumor size was monitored using contrast enhanced T1-weighted MRI in both treated and control rats at several time points (4, 6, 11, 18 and 32 days post tumor inoculation). RESULTS CNS1 cells are sensitive to radiation in vitro, as cell survival decreased after exposure to increasing amounts of radiation. In vivo, while initial tumor size did not significantly differ between groups, rats treated with radiation survived significantly longer than control rats (23.8 ± 5.0 days vs. 11 ± 4.1 days, p<0.005). Growth arrest following irradiation in vivo was not detected 1d after treatment but was observed 6d post-irradiation. Growth arrest was recorded in half of the treated rats, showing no increase in tumor size (N=2) or reduction in tumor volume (N=1) relative to 1d post-irradiation. Tumor growth rates were lower in all irradiated rats relative to control rats. Survival time was negatively correlated with initial tumor size in the control group but not in the treatment group. CONCLUSION CNS1 rat model of GBM is a valid model of radiotherapy effects on GBM tumors. Further studies combining radiation and chemotherapy are the next step. Support for this work was provided by Israel Cancer Association.

Endothelin-1 and pancreatic islet vasculature: studies in vivo and on isolated, vascularly perfused pancreatic islets

2007 ◽  
Vol 292 (6) ◽  
pp. E1616-E1623 ◽  
Author(s):  
En Yin Lai ◽  
A. Erik G. Persson ◽  
Birgitta Bodin ◽  
Örjan Källskog ◽  
Arne Andersson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pancreatic Islet ◽  
Vascular Reactivity ◽  
Blood Perfusion ◽  
Receptor Subtype ◽  
Endothelin 1 ◽  
Islet Blood Flow ◽  
Endothelin B

Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor, which also stimulates insulin release. The aim of the present study was to evaluate whether exogenously administered ET-1 affected pancreatic islet blood flow in vivo in rats and the islet arteriolar reactivity in vitro in mice. Furthermore, we aimed to determine the ET-receptor subtype that was involved in such responses. When applying a microsphere technique for measurements of islet blood perfusion in vivo, we found that ET-1 (5 nmol/kg) consistently and markedly decreased total pancreatic and especially islet blood flow, despite having only minor effects on blood pressure. Neither endothelin A (ETA) receptor (BQ-123) nor endothelin-B (ETB) receptor (BQ-788) antagonists, alone or in combination, could prevent this reduction in blood flow. To avoid confounding interactions in vivo, we also examined the arteriolar vascular reactivity in isolated, perfused mouse islets. In the latter preparation, we demonstrated a dose-dependent constriction in response to ET-1. Administration of BQ-123 prevented this, whereas BQ-788 induced a right shift in the response. In conclusion, the pancreatic islet vasculature is highly sensitive to exogenous ET-1, which mediates its effect mainly through ETA receptors.

Neuronal intermediate filament expression in rat dorsal root ganglia sensory neurons: An in vivo and in vitro study

Neuroscience ◽  
2008 ◽  
Vol 153 (4) ◽  
pp. 1153-1163 ◽  
Author(s):  
M. Fornaro ◽  
J.M. Lee ◽  
S. Raimondo ◽  
S. Nicolino ◽  
S. Geuna ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Dorsal Root Ganglia ◽  
Intermediate Filament ◽  
Dorsal Root ◽  
In Vitro Study ◽  
Vitro Study

scholarly journals Myelin-specific proteins and glycolipids in rat Schwann cells and oligodendrocytes in culture.

1980 ◽  
Vol 84 (3) ◽  
pp. 483-494 ◽  
Author(s):  
R Mirsky ◽  
J Winter ◽  
E R Abney ◽  
R M Pruss ◽  
J Gavrilovic ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Schwann Cells ◽  
Dorsal Root ◽  
Basic Protein ◽  
Intrinsic Properties ◽  
Short Term ◽  
Explant Cultures ◽  
Specific Proteins

We have used antibodies to identify Schwann cells and oligodendrocytes and to study the expression of myelin-specific glycolipids and proteins in these cells isolated from perinatal rats. Our findings suggest that only Schwann cells which have been induced to myelinate make detectable amounts of galactocerebroside (GC), sulfatide, myelin basic protein (BP), or the major peripheral myelin glycoprotein (P0). When rat Schwann cells were cultured, they stopped making detectable amounts of these myelin molecules, even when the cells were associated with neurites in short-term explant cultures of dorsal root ganglion. In contrast, oligodendrocytes in dissociated cell cultures of neonatal optic nerve, corpus callosum, or cerebellum continued to make GC, sulfatide and BP for many weeks, even in the absence of neurons. These findings suggest that while rat Schwann cells require a continuing signal from appropriate axons to make detectable amounts of myelin-specific glycolipids and proteins, oligodendrocytes do not. Schwann cells and oligodendrocytes also displayed very different morphologies in vitro which appeared to reflect their known differences in myelinating properties in vivo. Since these characteristic morphologies are maintained when Schwann cells and oligodendrocytes were grown together in mixed cultures and in the absence of neurons, we concluded that they are intrinsic properties of these two different myelin-forming cells.

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