scholarly journals Locating the Site of Neuropathic Pain In Vivo Using MMP-12-Targeted Magnetic Nanoparticles

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Syeda Fabeha Husain ◽  
Raymond W. M. Lam ◽  
Tao Hu ◽  
Michael W. F. Ng ◽  
Z. Q. G. Liau ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Magnetic Resonance ◽  
Intrathecal Injection ◽  
Thermal Hyperalgesia ◽  
Spinal Nerve ◽  
Iron Oxide Nanoparticle ◽  
Anatomical Location ◽  
Spinal Nerves ◽  
Potential Biomarker

Neuropathic pain remains underrecognised and ineffectively treated in chronic pain sufferers. Consequently, their quality of life is considerably reduced, and substantial healthcare costs are incurred. The anatomical location of pain must be identified for definitive diagnosis, but current neuropsychological tools cannot do so. Matrix metalloproteinases (MMP) are thought to maintain peripheral neuroinflammation, and MMP-12 is elevated particularly in such pathological conditions. Magnetic resonance imaging (MRI) of the peripheral nervous system has made headway, owing to its high-contrast resolution and multiplanar features. We sought to improve MRI specificity of neural lesions, by constructing an MMP-12-targeted magnetic iron oxide nanoparticle (IONP). Its in vivo efficiency was evaluated in a rodent model of neuropathic pain, where the left lumbar 5 (L5) spinal nerve was tightly ligated. Spinal nerve ligation (SNL) successfully induced mechanical allodynia, and thermal hyperalgesia, in the left hind paw throughout the study duration. These neuropathy characteristics were absent in animals that underwent sham surgery. MMP-12 upregulation with concomitant macrophage infiltration, demyelination, and elastin fibre loss was observed at the site of ligation. This was not observed in spinal nerves contralateral and ipsilateral to the ligated spinal nerve or uninjured left L5 spinal nerves. The synthesised MMP-12-targeted magnetic IONP was stable and nontoxic in vitro. It was administered onto the left L5 spinal nerve by intrathecal injection, and decreased magnetic resonance (MR) signal was observed at the site of ligation. Histology analysis confirmed the presence of iron in ligated spinal nerves, whereas iron was not detected in uninjured left L5 spinal nerves. Therefore, MMP-12 is a potential biomarker of neuropathic pain. Its detection in vivo, using IONP-enhanced MRI, may be further developed as a tool for neuropathic pain diagnosis and management.

scholarly journals Oral Gabapentin Activates Spinal Cholinergic Circuits to Reduce Hypersensitivity after Peripheral Nerve Injury and Interacts Synergistically with Oral Donepezil

2007 ◽  
Vol 106 (6) ◽  
pp. 1213-1219 ◽  
Author(s):  
Ken-ichiro Hayashida ◽  
Renée Parker ◽  
James C. Eisenach
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Intrathecal Injection ◽  
Spinal Nerve ◽  
Male Rats ◽  
Additive Interaction ◽  
Alzheimer Dementia ◽  
Routes Of Administration ◽  
Withdrawal Threshold ◽  
The Brain

Background Gabapentin administration into the brain of mice reduces nerve injury-induced hypersensitivity and is blocked by intrathecal atropine and enhanced by intrathecal neostigmine. The authors tested the relevance of these findings to oral therapy by examining the efficacy of oral gabapentin to reduce hypersensitivity after nerve injury in rats and its interaction with the clinically used cholinesterase inhibitor, donepezil. Methods Male rats with hypersensitivity after spinal nerve ligation received gabapentin orally, intrathecally, and intracerebroventricularly with or without intrathecal atropine, and withdrawal threshold to paw pressure was determined. The effects of oral gabapentin and donepezil alone and in combination on withdrawal threshold were determined in an isobolographic design. Results Gabapentin reduced hypersensitivity to paw pressure by all routes of administration, and was more potent and with a quicker onset after intracerebroventricular than intrathecal injection. Intrathecal atropine reversed the effect of intracerebroventricular and oral gabapentin. Oral gabapentin and donepezil interacted in a strongly synergistic manner, with an observed efficacy at one tenth the predicted dose of an additive interaction. The gabapentin-donepezil combination was reversed by intrathecal atropine. Conclusions Although gabapentin may relieve neuropathic pain by actions at many sites, these results suggest that its actions in the brain to cause spinal cholinergic activation predominate after oral administration. Side effects, particularly nausea, cannot be accurately determined on rats. Nevertheless, oral donepezil is well tolerated by patients in the treatment of Alzheimer dementia, and the current study provides the rationale for clinical study of combination of gabapentin and donepezil to treat neuropathic pain.

scholarly journals Usefulness of Olanzapine as an Adjunct to Opioid Treatment and for the Treatment of Neuropathic Pain

2012 ◽  
Vol 116 (1) ◽  
pp. 159-169 ◽  
Author(s):  
Kazuhiro Torigoe ◽  
Kae Nakahara ◽  
Mahardian Rahmadi ◽  
Kazumi Yoshizawa ◽  
Hiroshi Horiuchi ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Sleep Disturbance ◽  
Brain Tissue ◽  
Gastrointestinal Transit ◽  
Thermal Hyperalgesia ◽  
Nausea And Vomiting ◽  
Dependent Manner ◽  
Antiemetic Effect

Background The use of opioids for pain management is often associated with nausea and vomiting. Although conventional antipsychotics are often used to counter emesis, they can be associated with extrapyramidal symptoms. However, chronic pain can induce sleep disturbance. The authors investigated the effects of the atypical antipsychotic olanzapine on morphine-induced emesis and the sleep dysregulation associated with chronic pain. Methods A receptor binding assay was performed using mouse whole brain tissue. The emetic response in ferrets was evaluated by counting retching and vomiting behaviors. Catalepsy in mice was evaluated by placing both of their forepaws over a horizontal bar. Released dopamine was measured by an in vivo microdialysis study. Sleep disturbance in mice in a neuropathic pain-like state was assayed by electroencephalogram and electromyogram recordings. Results Olanzapine showed high affinity for muscarinic M1 receptor in brain tissue. Olanzapine decreased morphine-induced nausea and vomiting in a dose-dependent manner. However, olanzapine at a dose that had an antiemetic effect (0.03 mg/kg) did not induce catalepsy or hyperglycemia. In addition, olanzapine at this dose had no effect on the morphine-induced release of dopamine or inhibition of gastrointestinal transit. Finally, olanzapine inhibited thermal hyperalgesia and completely alleviated the sleep disturbance induced by sciatic nerve ligation. Conclusion These findings suggest that olanzapine may be useful for the treatment of morphine-induced emesis and as an adjunct for the treatment of neuropathic pain associated with sleep disturbance.

scholarly journals Imaging Neuroinflammation In Vivo in a Neuropathic Pain Rat Model with Near-Infrared Fluorescence and 19F Magnetic Resonance

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e90589 ◽  
Author(s):  
Kiran Vasudeva ◽  
Karl Andersen ◽  
Bree Zeyzus-Johns ◽  
T. Kevin Hitchens ◽  
Sravan Kumar Patel ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Magnetic Resonance ◽  
Rat Model ◽  
Near Infrared ◽  
Near Infrared Fluorescence

scholarly journals Loss of SNHG4 Attenuated Spinal Nerve Ligation-Triggered Neuropathic Pain through Sponging miR-423-5p

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Xia Pan ◽  
Cheng Shen ◽  
Yayi Huang ◽  
Long Wang ◽  
Zhongyuan Xia ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Molecular Mechanisms ◽  
Thermal Hyperalgesia ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Rat Models ◽  
Tnf Α ◽  
Cord Injury ◽  
Gene 4 ◽  
Nucleolar Rna

Neuropathic pain is an intractable comorbidity of spinal cord injury. Increasing noncoding RNAs have been implicated in neuropathic pain development. lncRNAs have been recognized as significant regulators of neuropathic pain. lncRNA Small Nucleolar RNA Host Gene 4 (SNHG4) is associated with several tumors. However, the molecular mechanisms of SNHG4 in neuropathic pain remain barely documented. Here, we evaluated the function of SNHG4 in spinal nerve ligation (SNL) rat models. We observed that SNHG4 was significantly upregulated in SNL rat. Knockdown of SNHG4 was able to attenuate neuropathic pain progression via regulating behaviors of neuropathic pain including mechanical and thermal hyperalgesia. Moreover, knockdown of SNHG4 could repress the neuroinflammation via inhibiting IL-6, IL-12, and TNF-α while inducing IL-10 levels. Additionally, miR-423-5p was predicted as the target of SNHG4 by employing bioinformatics analysis. miR-423-5p has been reported to exert significantly poorer in several diseases. However, the role of miR-423-5p in the development of neuropathic pain is needed to be clarified. Here, in our investigation, RIP assay confirmed the correlation between miR-423-5p and SNHG4. Meanwhile, we found that miR-423-5p was significantly decreased in SNL rat models. SNHG4 regulated miR-423-5p expression negatively. As exhibited, the loss of miR-423-5p contributed to neuropathic pain progression, which was rescued by the silence of SNHG4. Therefore, our study indicated SNHG4 as a novel therapeutic target for neuropathic pain via sponging miR-423-5p.

Spinal GABAAand GABABReceptor Pharmacology in a Rat Model of Neuropathic Pain

2002 ◽  
Vol 96 (5) ◽  
pp. 1161-1167 ◽  
Author(s):  
T. Philip Malan ◽  
Heriberto P. Mata ◽  
Frank Porreca
Keyword(s):  
Neuropathic Pain ◽  
Receptor Antagonist ◽  
Motor Function ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Thermal Hyperalgesia ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Tactile Allodynia ◽  
Withdrawal Latency

Background This study tests the hypothesis that loss of spinal activity of gamma-aminobutyric acid (GABA) contributes to the allodynia and hyperalgesia observed after peripheral nerve injury. Methods Intrathecal catheters were implanted in male Sprague-Dawley rats. Antinociception was assessed by measuring withdrawal latency to immersion of the tail in a 52 degrees C water bath. Nerve injury was produced by ligation of the L5 and L6 spinal nerves. Testing was performed 4-14 days after spinal nerve ligation, when tactile allodynia and thermal hyperalgesia were established. Tactile allodynia was quantitated using the threshold to withdrawal of the hind paw on probing with von Frey filaments. Thermal hyperalgesia was quantitated using the latency to withdrawal of the hind paw from radiant heat. Motor function was tested using a rotarod apparatus. Results Spinal administration of the GABAA receptor antagonist bicuculline or the GABAB receptor antagonist phaclofen produced tactile allodynia and thermal hyperalgesia in normal rats. The GABAB receptor agonist baclofen, administered spinally, produced antinociception in the tail-flick test, whereas the GABAA receptor agonist isoguvacine did not. Isoguvacine and baclofen each reversed tactile allodynia and thermal hyperalgesia produced by spinal nerve ligation. Baclofen but not isoguvacine prolonged thermal withdrawal latency in nerve-injured rats beyond preoperative values. Baclofen but not isoguvacine impaired motor function. Conclusions Pharmacologic inhibition of intrinsic GABA tone in normal rats resulted in tactile allodynia and thermal hyperalgesia, consistent with the hypothesis being tested. Exogenous administration of GABA agonists reversed spinal nerve ligation-induced allodynia and hyperalgesia, also consistent with this hypothesis. Isoguvacine produced specific antihyperalgesic and antiallodynic effects, whereas assessment of the effects of baclofen was complicated by motor dysfunction. Spinal GABAA agonists may provide a specific therapy for neuropathic pain.

scholarly journals Urotensin II inhibitor eases neuropathic pain by suppressing the JNK/NF-κB pathway

2017 ◽  
Vol 232 (2) ◽  
pp. 165-174 ◽  
Author(s):  
Jing Li ◽  
Pan-Pan Zhao ◽  
Ting Hao ◽  
Dan Wang ◽  
Yu Wang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Cyclic Peptide ◽  
Intrathecal Injection ◽  
Thermal Hyperalgesia ◽  
Nuclear Factor Κb ◽  
Neurosecretory System ◽  
Urotensin Ii ◽  
Caudal Neurosecretory System

Urotensin II (U-II), a cyclic peptide originally isolated from the caudal neurosecretory system of fishes, can produce proinflammatory effects through its specific G protein-coupled receptor, GPR14. Neuropathic pain, a devastating disease, is related to excessive inflammation in the spinal dorsal horn. However, the relationship between U-II and neuropathic pain has not been reported. This study was designed to investigate the effect of U-II antagonist on neuropathic pain and to understand the associated mechanisms. We reported that U-II and its receptor GPR14 were persistently upregulated and activated in the dorsal horn of L4–6 spinal cord segments after chronic constriction injury (CCI) in rats. Intrathecal injection of SB657510, a specific antagonist against U-II, reversed CCI-induced thermal hyperalgesia and mechanical allodynia. Furthermore, we found that SB657510 reduced the expression of phosphorylated c-Jun N-terminal kinase (p-JNK) and nuclear factor-κB (NF-κB) p65 as well as subsequent secretion of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α). It was also showed that both the JNK inhibitor SP600125 and the NF-κB inhibitor PDTC significantly attenuated thermal hyperalgesia and mechanical allodynia in CCI rats. Our present research showed that U-II receptor antagonist alleviated neuropathic pain possibly through the suppression of the JNK/NF-κB pathway in CCI rats, which will contribute to the better understanding of function of U-II and pathogenesis of neuropathic pain.

scholarly journals Protocatechuic acid as an inhibitor of the JNK/CXCL1/CXCR2 pathway relieves neuropathic pain in CCI rats

2021 ◽  
Author(s):  
Hong-xia Chang ◽  
Yue-feng Zhao
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Satellite Cells ◽  
Protocatechuic Acid ◽  
Thermal Hyperalgesia ◽  
Tnf Α ◽  
Chemokine Ligand ◽  
New Perspective

Emerging evidence has shown that protocatechuic acid (PCA) has antioxidant and anti-inflammatory effects. Evidence suggests that PCA can alleviate the injury of sciatic nerve, while the mechanism of its therapeutic effect on neuralgia remains unknown.         Chromium bowel ligation was used in vivo to establish a chronic constriction injury (CCI) rat model to induce sciatic nerve pain. Subsequently, two doses of PCA were used to treat CCI rats. In vitro, 10 ng/mL TNF-α was used to stimulate glial satellite cells derived from the dorsal root ganglia (DRG) L4-L6 of the sciatic nerve to simulate sciatic nerve pain. PCA relieved mechanical allodynia and thermal hyperalgesia in CCI rats. CCK-8 assay revealed that PCA inhibited the proliferation of glial satellite cells induced by TNF-α. Moreover, ELISA demonstrated that PCA could improve the inflammatory response of rats caused by CCI and cells induced by TNF-α. Next, RT-qPCR and Western blot assays showed that PCA blocked the c-Jun N-terminal kinase/the chemokine ligand 1/CXC chemokine receptor 2 (JNK/CXCL1/CXCR2) pathway by inhibiting CXCL1 levels in cells induced by TNF-α and DRG in CCI rats. In conclusion, PCA can alleviate neuropathic pain in CCI rats and improve oxidative stress by inhibiting the JNK/CXCL1/CXCR2 signaling pathway. Thus, these findings provide a new perspective for the treatment of neuropathic pain caused by CCI.

scholarly journals Isotalatizidine, a C19-diterpenoid alkaloid, attenuates chronic neuropathic pain through stimulating ERK/CREB signaling pathway-mediated microglial dynorphin A expression

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Shuai Shao ◽  
Huan Xia ◽  
Min Hu ◽  
Chengjuan Chen ◽  
Junmin Fu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Lateral Roots ◽  
Intrathecal Injection ◽  
Dependent Manner ◽  
Dynorphin A ◽  
Diterpenoid Alkaloid ◽  
P38 Inhibitor ◽  
In Vivo Experiments ◽  
Underlying Mechanisms

Abstract Background Isotalatizidine is a representative C19-diterpenoid alkaloid extracted from the lateral roots of Aconitum carmichaelii, which has been widely used to treat various diseases on account of its analgesic, anti-inflammatory, anti-rheumatic, and immunosuppressive properties. The aim of this study was to evaluate the analgesic effect of isotalatizidine and its underlying mechanisms against neuropathic pain. Methods A chronic constrictive injury (CCI)-induced model of neuropathic pain was established in mice, and the limb withdrawal was evaluated by the Von Frey filament test following isotalatizidine or placebo administration. The signaling pathways in primary or immortalized microglia cells treated with isotalatizidine were analyzed by Western blotting and immunofluorescence. Results Intrathecal injection of isotalatizidine attenuated the CCI-induced mechanical allodynia in a dose-dependent manner. At the molecular level, isotalatizidine selectively increased the phosphorylation of p38 and ERK1/2, in addition to activating the transcription factor CREB and increasing dynorphin A production in cultured primary microglia. However, the downstream effects of isotalatizidine were abrogated by the selective ERK1/2 inhibitor U0126-EtOH or CREB inhibitor of KG-501, but not by the p38 inhibitor SB203580. The results also were confirmed in in vivo experiments. Conclusion Taken together, isotalatizidine specifically activates the ERK1/2 pathway and subsequently CREB, which triggers dynorphin A release in the microglia, eventually leading to its anti-nociceptive action.

Effect of Methylprednisolone on Neuropathic Pain and Spinal Glial Activation in Rats

2004 ◽  
Vol 100 (5) ◽  
pp. 1249-1257 ◽  
Author(s):  
Kenji Takeda ◽  
Shigehito Sawamura ◽  
Hiroshi Sekiyama ◽  
Hisayoshi Tamai ◽  
Kazuo Hanaoka
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Day Treatment ◽  
Thermal Hyperalgesia ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Glial Activation ◽  
Pain State ◽  
Protein Immunoreactivity ◽  
Neuropathic Pain State

Background Basic data are lacking regarding the efficacy and mechanisms of action of corticosteroids in neuropathic pain. Because recent studies indicate that spinal glial activation mediates the pathologic pain states, the authors sought to determine the effects of systemic and intrathecal methylprednisolone on the development and maintenance of neuropathic pain and spinal glial activation in a rat model. Methods Rats were anesthetized, and L5 and L6 spinal nerves were tightly ligated. Then, continuous infusion of systemic (4 mg x kg(-1) x day(-1)) or intrathecal (80 microg x kg(-1) x day(-1)) methylprednisolone or saline was started. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively with von Frey and Hargreaves tests, respectively. Spinal astrocytic activation was evaluated with glial fibrillary acidic protein immunoreactivity on day 7. In other groups of rats, continuous 3-day treatment with intrathecal methylprednisolone or saline was started 7 days after spinal nerve ligation, when neuropathic pain had already developed. Behavioral tests and immunostaining were performed up to 3 weeks after the treatment. Results Spinal nerve ligation induced mechanical allodynia and thermal hyperalgesia on days 4 and 7 postoperatively. Glial fibrillary acidic protein immunoreactivity was remarkably enhanced on day 7. Both systemic and intrathecal methylprednisolone inhibited the development of neuropathic pain states and glial activation. Three-day treatment with intrathecal methylprednisolone reversed existing neuropathic pain state and glial activation up to 3 weeks after the treatment. Conclusion : Systemic and intrathecal methylprednisolone inhibited spinal glial activation and the development and maintenance of a neuropathic pain state in a rat model of spinal nerve ligation.

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