Upregulation of the T-Type Calcium Current in Small Rat Sensory Neurons After Chronic Constrictive Injury of the Sciatic Nerve

Recent data indicate that peripheral T-type Ca2+ channels are instrumental in supporting acute pain transmission. However, the function of these channels in chronic pain processing is less clear. To address this issue, we studied the expression of T-type Ca2+ currents in small nociceptive dorsal root ganglion (DRG) cells from L4-5 spinal ganglia of adult rats with neuropathic pain due to chronic constrictive injury (CCI) of the sciatic nerve. In control rats, whole cell recordings revealed that T-type currents, measured in 10 mM Ba2+ as a charge carrier, were present in moderate density (20 ± 2 pA/pF). In rats with CCI, T-type current density (30 ± 3 pA/pF) was significantly increased, but voltage- and time-dependent activation and inactivation kinetics were not significantly different from those in controls. CCI-induced neuropathy did not significantly change the pharmacological sensitivity of T-type current in these cells to nickel. Collectively, our results indicate that CCI-induced neuropathy significantly increases T-type current expression in small DRG neurons. Our finding that T-type currents are upregulated in a CCI model of peripheral neuropathy and earlier pharmacological and molecular studies suggest that T-type channels may be potentially useful therapeutic targets for the treatment of neuropathic pain associated with partial mechanical injury to the sciatic nerve.

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Bogijetong Decoction and Its Selected Formulation Are Involved in Alleviating Neuropathic Pain in a Rat Model of Chronic Constrictive Injury

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/2050636 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Ki-Joong Kim ◽

Hye-Jeong Ahn ◽

Uk Namgung ◽

Chung Sik Cho

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Neurite Outgrowth ◽

Neuronal Cell ◽

Treated Group ◽

Neuronal Cell Body ◽

Molecular Response ◽

Drg Neurons ◽

Chronic Constrictive Injury

Bogijetong decoction (BGJTD) is a formulation that is used for the treatment of neuropathic pain caused by cancer therapy, diabetes, and peripheral nerve injury. In the previous study, we selected four herbal constituents from BGJTD, formulated new decoction (BeD), and demonstrated its efficacy on the neuroprotection of peripheral sciatic nerve in streptozotocin-induced diabetic animals. Here, we report attenuating effects of BGJTD and BeD on neuropathic pain. Neuropathic pain was induced by ligation of the sciatic nerve to generate chronic constrictive injury (CCI). BeD was more effective than BGJTD in alleviating neuropathic pain lasting 3 – 4 weeks after CCI. In vivo administration of BeD did not alter the levels of brain-derived neurotrophic factor (BDNF) which were strongly induced by CCI in the sciatic nerve but downregulated TrkB production in the sciatic nerve. Downregulation of TrkB signals by BeD was confirmed in cultured DRG neurons. BGJTD was more effective in attenuating TNF-α production in the sciatic nerve than BeD, whereas BeD increased IL-6 more efficiently than BGJTD. Furthermore, phopsho-Erk1/2 was increased in the sciatic nerve and dorsal root ganglia (DRG) after BeD treatment. Neurite outgrowth of primary DRG neurons prepared from rats which had undergone CCI for 7 days was significantly increased in BeD-treated group of animals compared to the control and BGJTD-treated groups. Compositional comparison of BeD revealed that the neurite outgrowth was facilitated by the treatments of Panax ginseng and Paeonia lactiflora. Together, these data suggest that BeD induces unique molecular response at the injury site and may trigger retrograde signaling into the neuronal cell body to modulate pain responses.

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SIRT1 Mediates Neuropathic Pain Induced by Sciatic Nerve Chronic Constrictive Injury in the VTA-NAc Pathway

Pain Research and Management ◽

10.1155/2020/4245968 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Yangyang Li ◽

Lei Wang ◽

Guotao Zhang ◽

Xueli Qiao ◽

Mingxing Zhang

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Dorsal Root ◽

Elevated Level ◽

Thermal Hyperalgesia ◽

Sirtuin 1 ◽

Class Iii ◽

Histone 3 ◽

Chronic Constrictive Injury

Background. Mounting evidence has shown that sirtuin 1 (SIRT1), a class III histone deacetylase, alleviated several types of neuropathic pain in the spinal cord and dorsal root ganglion and regulated some aberrant behaviors in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Methods. In this context, the effect of SIRT1 on neuropathic pain in the VTA-NAc pathway was investigated in the model of chronic constrictive injury (CCI). Results. SIRT1 was localized in the VTA neurons in naive mice. The expression of SIRT1 was decreased in the contralateral VTA of CCI mice. After microinjection of SRT1720 (an activator of SIRT1) in the contralateral VTA of CCI mice, the established thermal hyperalgesia was attenuated. However, it was further exacerbated by EX-527 (an inhibitor of SIRT1). The elevated level of acetyl-histone 3 was reduced by SRT1720 but further elevated by EX-527 in the contralateral VTA of CCI mice. The increased expression of Fos in both VTA and NAc was downregulated by SRT1720 but further upregulated by EX-527 in CCI mice. Conclusions. The discovery of the effect of SIRT1 on neuropathic pain in the VTA represents an important step forward in understanding the analgesic mechanisms of the VTA-NAc pathway.

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Upregulation of a Silent Sodium Channel After Peripheral, but not Central, Nerve Injury in DRG Neurons

Journal of Neurophysiology ◽

10.1152/jn.1999.82.5.2776 ◽

1999 ◽

Vol 82 (5) ◽

pp. 2776-2785 ◽

Cited By ~ 203

Author(s):

J. A. Black ◽

T. R. Cummins ◽

C. Plumpton ◽

Y. H. Chen ◽

W. Hormuzdiar ◽

...

Keyword(s):

Sciatic Nerve ◽

Sodium Channel ◽

Sodium Channels ◽

Sodium Current ◽

Sodium Currents ◽

Drg Neurons ◽

Adult Rats ◽

Voltage Range ◽

Type Iii ◽

Axonal Projections

After transection of their axons within the sciatic nerve, DRG neurons become hyperexcitable. Recent studies have demonstrated the emergence of a rapidly repriming tetrodotoxin (TTX)-sensitive sodium current that may account for this hyperexcitability in axotomized small (<27 μm diam) DRG neurons, but its molecular basis has remained unexplained. It has been shown previously that sciatic nerve transection leads to an upregulation of sodium channel III transcripts, which normally are present at very low levels in DRG neurons, in adult rats. We show here that TTX-sensitive currents in small DRG neurons, after transection of their peripheral axonal projections, reprime more rapidly than those in control neurons throughout a voltage range of −140 to −60 mV, a finding that suggests that these currents are produced by a different sodium channel. After transection of the central axonal projections (dorsal rhizotomy) of these small DRG neurons, in contrast, the repriming kinetics of TTX-sensitive sodium currents remain similar to those of control (uninjured) neurons. We also demonstrate, with two distinct antibodies directed against different regions of the type III sodium channel, that small DRG neurons display increased brain type III immunostaining when studied 7–12 days after transection of their peripheral, but not central, projections. Type III sodium channel immunoreactivity is present within somata and neurites of peripherally axotomized, but not centrally axotomized, neurons studied after <24 h in vitro. Peripherally axotomized DRG neurons in situ also exhibit enhanced type III staining compared with control neurons, including an accumulation of type III sodium channels in the distal portion of the ligated and transected sciatic nerve, but these changes are not seen in centrally axotomized neurons. These observations are consistent with a contribution of type III sodium channels to the rapidly repriming sodium currents observed in peripherally axotomized DRG neurons and suggest that type III channels may at least partially account for the hyperexcitibility of these neurons after injury.

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Interactions between Autophagy, Proinflammatory Cytokines and Apoptosis in Neuropathic Pain: Granulocyte Colony Stimulating Factor as a Multipotent Therapy in Rats with Chronic Constriction Injury

Biomedicines ◽

10.3390/biomedicines9050542 ◽

2021 ◽

Vol 9 (5) ◽

pp. 542

Author(s):

Ming-Feng Liao ◽

Shin-Rung Yeh ◽

Kwok-Tung Lu ◽

Jung-Lung Hsu ◽

Po-Kuan Chao ◽

...

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Protein Expression ◽

Proinflammatory Cytokines ◽

Early Phase ◽

Chronic Constriction Injury ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Drg Neurons ◽

Stimulating Factor

Our previous studies have shown that early systemic granulocyte colony-stimulating factor (G-CSF) treatment can attenuate neuropathic pain in rats with chronic constriction injury (CCI) by modulating expression of different proinflammatory cytokines, microRNAs, and proteins. Besides the modulation of inflammatory mediators’ expression, previous studies have also reported that G-CSF can modulate autophagic and apoptotic activity. Furthermore, both autophagy and apoptosis play important roles in chronic pain modulation. In this study, we evaluated the temporal interactions of autophagy, and apoptosis in the dorsal root ganglion (DRG) and injured sciatic nerve after G-CSF treatment in CCI rats. We studied the behaviors of CCI rats with or without G-CSF treatment and the various levels of autophagic, proinflammatory, and apoptotic proteins in injured sciatic nerves and DRG neurons at different time points using Western blot analysis and immunohistochemical methods. The results showed that G-CSF treatment upregulated autophagic protein expression in the early phase and suppressed apoptotic protein expression in the late phase after nerve injury. Thus, medication such as G-CSF can modulate autophagy, apoptosis, and different proinflammatory proteins in the injured sciatic nerve and DRG neurons, which have the potential to treat neuropathic pain. However, autophagy-mediated regulation of neuropathic pain is a time-dependent process. An increase in autophagic activity in the early phase before proinflammatory cytokines reach the threshold level to induce neuropathic pain can effectively alleviate further neuropathic pain development.

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Retrograde Labeling of Different Distribution Features of DRG P2X2 and P2X3 Receptors in a Neuropathic Pain Rat Model

BioMed Research International ◽

10.1155/2020/9861459 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Lin Chen ◽

Changlong Leng ◽

Qin Ru ◽

Qi Xiong ◽

Mei Zhou ◽

...

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Rat Model ◽

Dorsal Root ◽

Chronic Constriction Injury ◽

P2x Receptors ◽

Drg Neurons ◽

P2x3 Receptors ◽

Peripheral Neuropathic Pain ◽

Distribution Features

The distributions of P2X subtypes during peripheral neuropathic pain conditions and their differential roles are not fully understood. To explore these characteristics, the lumbosacral dorsal root ganglion (DRG) in the chronic constriction injury (CCI) sciatic nerve rat model was studied. Retrograde trace labeling combined with immunofluorescence technology was applied to analyze the distribution of neuropathic nociceptive P2X1-6 receptors. Our results suggest that Fluoro-Gold (FG) retrograde trace labeling is an efficient method for studying lumbosacral DRG neurons in the CCI rat model, especially when the DRG neurons are divided into small, medium, and large subgroups. We found that neuropathic nociceptive lumbosacral DRG neurons (i.e., FG-positive cells) were significantly increased in medium DRG neurons, while they declined in the large DRG neurons in the CCI group. P2X3 receptors were markedly upregulated in medium while P2X2 receptors were significantly decreased in small FG-positive DRG neurons. There were no significant changes in other P2X receptors (including P2X1, P2X4, P2X5, and P2X6). We anticipate that P2X receptors modulate nociceptive sensitivity primarily through P2X3 subtypes that are upregulated in medium neuropathic nociceptive DRG neurons and/or via the downregulation of P2X2 cells in neuropathic nociceptive small DRG neurons.

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Prevention and Healing of Calcium Signaling Mediated Neuronal Damage on successive Administration of Flavonoid Enriched Pterocarpus Marsupium Roxb in Peripheral Neuropathy Model

Current Bioactive Compounds ◽

10.2174/1573407216666200218112305 ◽

2020 ◽

Vol 16 (9) ◽

pp. 1346-1355

Author(s):

Neethi Shaju ◽

Mrinmoy Gautam ◽

Abdul Khayum ◽

Gunasekaran Venkatesh

Keyword(s):

Neuropathic Pain ◽

Peripheral Neuropathy ◽

Sciatic Nerve ◽

Motor Neurons ◽

Neuronal Damage ◽

Interleukin 10 ◽

Central Mechanism ◽

Behavioral Models ◽

Cell Hyperplasia ◽

Pterocarpus Marsupium

Background: Modern research on peripheral neuropathy circumstance utter that treatments with Vincristine (VCR) disturb the microtubular cells in sensory and motor neurons due to calcium over- load in sciatic nerve, unfortunately, VCR triggering the release of Tumor necrosis factor-α (TNFα) in central neurons causes excitotoxicity as well. Although ethnomedical information specifies that Pterocarpus marsupium Roxb (PM) is widely used for various nervous disorders, not yet justified on VCR induced peripheral neuropathy and in relation to central mechanism. Objective: This study is aimed to explore the possible central and peripheral mechanism of flavonoid enriched PM in VCR induced neuropathy model. Methods: Neuropathic pain was induced in female Wistar rats by VCR (75μg/ kg/day, i.p) for 10 days. Nociceptive thresholds were assessed by subjecting them to behavioral and biochemical estimation, proinflammatory cytokines along with morphological evaluation. Results: PM significantly increased the nociceptive threshold evident from various behavioral models in comparison to VCR group. More importantly, PM significantly reversed the VCR induced calcium elevation, glutamate and aspartate release in the brain. Discussion: It was also observed that the raised TNF-α, Interleukin-1β were controlled and interleukin- 10 was elevated in sciatic nerve after PM treatment. Evident from histology, PM markedly reversed the VCR induced axonal degeneration, Schwann cell hyperplasia, and myelin fibrosis. Conclusion: Flavonoid enriched PM both 100 & 200mg/kg post and co-administration exerted a preventive and curative effect in VCR induced neuropathic pain by controlling calcium-mediated excitotoxicity through peripheral and central mechanism.

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Alpha lipoic acid attenuated neuropathic pain induced by chronic constriction Injury of sciatic nerve in rats

Clinical Phytoscience ◽

10.1186/s40816-021-00263-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Prasad Neerati ◽

Harika Prathapagiri

Keyword(s):

Neuropathic Pain ◽

Peripheral Neuropathy ◽

Sciatic Nerve ◽

Lipoic Acid ◽

Normal Saline ◽

Chronic Constriction Injury ◽

Thermal Hyperalgesia ◽

Alpha Lipoic Acid ◽

Chronic Neuropathic Pain ◽

Neuropathic Pain Syndrome

Abstract Background Chronic neuropathic pain syndrome is associated with impaired quality of life and is poorly manageable. Alpha lipoic acid (ALA) is a powerful antioxidant and showed its effectiveness on diabetic neuropathy and other acute peripheral nerve injuries but it was not evaluated in the chronic neuropathic pain, chronic constriction injury (CCI) in rat model by using duloxetine (DLX) as standard. Methodology The main objective of the study was to expedite ALA effect on chronic peripheral neuropathy induced by CCI of sciatic nerve in rats. In this study, male Wister rats were randomly divided into six groups (n = 8) including, normal saline, sham operated, surgery control, DLX 30mg/kg treated, ALA treated 25mg/kg, and ALA+DLX. The CCI of sciatic nerve was conducted on all animals except normal saline group and studied for 21 days (i.e. 14 days treatment period & 7 days treatment free period) by using different behavioral, biochemical and, histopathology studies. Results ALA showed minor but significant decrease of thermal hyperalgesia, cold allodynia, malondialdehyde (MDA), total protein, lipid peroxidation, and nitric oxide levels and significant increase of motor coordination, glutathione level and decreased axonal degeneration significantly. These effects sustained even during treatment free period. ALA enhanced the effect of DLX when given in combination by showing sustained effect. In conclusion, ALA acted as potent antioxidant may be this activity is responsible for the potent neuroprotective effect. Conclusion Hence, ALA attenuated the nueroinflammation mediated by chronic peripheral neuropathy. Further studies are warranted with ALA to develop as a clinically relevant therapeutic agent for the treatment of neuropathic pain.

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SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury

Molecular Pain ◽

10.1177/17448069211006603 ◽

2021 ◽

Vol 17 ◽

pp. 174480692110066

Author(s):

Orest Tsymbalyuk ◽

Volodymyr Gerzanich ◽

Aaida Mumtaz ◽

Sanketh Andhavarapu ◽

Svetlana Ivanova ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Peripheral Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Thermal Sensitivity ◽

Gradual Improvement ◽

Pain Behaviors

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

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Interaction of NHE1 and TRPA1 activity in DRG neurons isolated from adult rats and its role in inflammatory nociception

Neuroscience ◽

10.1016/j.neuroscience.2021.04.025 ◽

2021 ◽

Author(s):

Vladimir A. Martínez-Rojas ◽

Ana B. Salinas-Abarca ◽

Norma L. Gómez-Víquez ◽

Vinicio Granados-Soto ◽

Francisco Mercado ◽

...

Keyword(s):

Drg Neurons ◽

Adult Rats ◽

Inflammatory Nociception

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Prevention of painful neuromas by oblique transection of peripheral nerves

Journal of Neurosurgery ◽

10.3171/jns.2006.104.2.285 ◽

2006 ◽

Vol 104 (2) ◽

pp. 285-289 ◽

Cited By ~ 18

Author(s):

Wieslaw Marcol ◽

Katarzyna Kotulska ◽

Magdalena Larysz-Brysz ◽

Grazyna Bierzyñska-Macyszyn ◽

Pawel Wlaszczuk ◽

...

Keyword(s):

Neuropathic Pain ◽

Sciatic Nerve ◽

Peripheral Nerves ◽

Traditional Method ◽

Healing Process ◽

Nerve Transection ◽

Proximal Stump ◽

Sciatic Nerves ◽

Neuroma Formation

Object Neuroma formation often occurs at the proximal stump of the transected nerve, complicating the healing process after gap injuries or nerve biopsies. Most such neuromas cause therapy-resistant neuropathic pain. The purpose of this study was to determine whether oblique transection of the proximal stump of the sciatic nerve can prevent neuroma formation. Methods The sciatic nerves of 10 rats were transected unilaterally at an angle of 30°, and the peripheral segments of the nerves were removed. In 10 control animals the sciatic nerves were transected at a perpendicular angle. Twenty weeks after surgery the nerves were reexposed and collected. The presence of neuromas was determined by two board-certified pathologists on the basis of histopathological evaluations. Conclusions The oblique transection of peripheral nerves, contrary to perpendicularly transected nerves, is rarely followed by classic neuroma development. Moreover, neuropathic pain is significantly reduced compared with that following the traditional method of nerve transection.

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