scholarly journals Control of Neonatal Spinal Networks by Nociceptors: A Potential Role for TRP Channel Based Therapies

2013 ◽  
Vol 16 (2) ◽  
pp. 313 ◽  
Author(s):  
Sravan Mandadi ◽  
Peter Hong ◽  
Arjun Sunny Dhoopar ◽  
Patrick Whelan
Keyword(s):  
Spinal Cord ◽  
Transient Receptor Potential ◽  
Pediatric Population ◽  
Receptor Potential ◽  
Basic Research ◽  
Spinal Pain ◽  
Mouse Genetics ◽  
Motor Dysfunction ◽  
Cord Injury ◽  
Nociceptive Afferents

Pediatric spinal cord injury (SCI) often leads to increased nociceptive input resulting in aberrant motor output like tremor and spasticity. Acute plasticity within spinal pain and motor networks following pediatric SCI may result in long-term sensorimotor disabilities. Despite this, pediatric SCI remains poorly understood. Part of the problem lies in the paucity of detailed studies aimed at defining sensorimotor control by nociceptors during development. This review provides an overview of work that highlights afferent control of sensorimotor networks by defined nociceptors in the developing spinal cord. Here, we focus on the well established and widely used neonatal sensorimotor model called sacrocaudal afferent (SCA) pathway. Until recently, the identity of specific subclasses of nociceptive afferents in the SCA pathway controlling developing sensorimotor networks was unknown. We highlight here the use of members of the Transient Receptor Potential (TRP) ion channels and mouse genetics to identify specific subsets of nociceptive afferents in the SCA pathway. In addition, we highlight the use of mouse genetics to map sensorimotor networks during development and potential future applications. A neonatal spinal cord model of central neuropathic pain via a defined set of nociceptors is presented as a probe into potential therapeutic avenues in neonatal SCI. Finally, knowledge translation from neonatal basic research to the pediatric population in the clinic is described. In conclusion, studies in neonatal models may lead to therapeutic strategies and pharmaceuticals for chronic pain and motor dysfunction after SCI during development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Polyphenols as Potential Therapeutics for Pain and Inflammation in Spinal Cord Injury

2020 ◽  
Vol 13 ◽  
Author(s):  
Ashif Iqubal ◽  
Musheer Ahmed ◽  
Mohammad Kashif Iqubal ◽  
Faheem Hyder Pottoo ◽  
Syed Ehtaishamul Haque
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Side Effects ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Neutrophil Infiltration ◽  
Matrix Metal ◽  
Mediators Of Inflammation ◽  
Major Player ◽  
Cord Injury

: Spinal cord injury (SCI) and associated pain and inflammation caused by the trauma or infection is one of the serious health care issues world-wide. The various inflammatory, redox-sensitive and apoptotic events are contributing factor but altered neuronal function, axonal degeneration, activated microglia, endothelial cells, astrocytes, fibroblasts,pericytes, Schwann cells, meningeal cells are the major player in its pathogenesis. Further, monocytes and neutrophil infiltration get recruited and facilitate the release of chemokines, cytokines, and other mediators of inflammation. This event leads to the production of different amino acids, neuropeptides kinin, prostaglandins, prostacyclin, thromboxane, leukotrienes, bradykinin, histamine, matrix metal proteinases and serotonin that stimulate nerve endings and manifests the inflammation and pain processes, etc. Arachidonic acid (AA), NF-kB, NLRP3 inflammasome, and nitric oxide pathways along with P2X7 receptor and ion channel transient receptor potential (TRP) vanilloid are some of the recently explored targets for modulation of pain and inflammation in SCI. Till now, NSAIDs, opioids, antidepressants, anticonvulsants, NMDA antagonists, α2-adrenergic agonists, and GABA-receptor agonists are used for the management of these pathological conditions. However, these drugs are associated with various side effects. Additionally, the number of available animal models for SCI has enhanced the understanding of the complex pathological mechanisms involved in the generation of chronic inflammatory pain in SCI. These findings enable us to identify and validate several potent natural analgesic-anti-inflammatory drug candidates with minimal side effects. However, until now, these compounds have been studied in preclinical models and shown promising results but no clinical studies have been performed. Therefore, a detailed exploration of these natural compounds is important for bringing them from bench to bedside.

Antihyperalgesic effects of vanilloid-1 and bradykinin-1 receptor antagonists following spinal cord injury in rats

2007 ◽  
Vol 6 (5) ◽  
pp. 420-424 ◽  
Author(s):  
Sharad Rajpal ◽  
Tiffany A. Gerovac ◽  
Nicholas A. Turner ◽  
Jessica I. Tilghman ◽  
Bradley K. Allcock ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Transient Receptor Potential ◽  
Treatment Strategies ◽  
Thermal Hyperalgesia ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Cord Injury ◽  
Bradykinin Antagonists ◽  
Transient Receptor

Object The authors previously discovered that genes for the bradykinin-1 (B1) receptor and the transient receptor potential vanilloid subtype 1 (TRPV1) were overexpressed in animals exhibiting thermal hyperalgesia (TH) following spinal cord injury (SCI). They now report the effect of TRPV1 (AMG9810) and B1 (Lys-[Des-Arg9, Leu8]-bradykinin) antagonists on TH in animals following SCI. Methods The rats were subjected to contusion SCI and then divided into groups in which TH did or did not develop. The animals from both groups were given either AMG9810, Lys-(Des-Arg9, Leu8)-bradykinin, or the drug-specific vehicle (control groups). Animals were tested for TH preinjury and at regular intervals after SCI by using the hindlimb withdrawal latency test. Conclusions The administration of AMG9810 likely improves TH as a result of a generalized analgesic effect, whereas the effect of Lys-(Des-Arg9, Leu8)-bradykinin appears more specific to the reversal of TH. This information has potential usefulness in the development of treatment strategies for post-SCI neuropathic pain.

scholarly journals 17β-Estradiol Inhibits MMP-9 and SUR1/TrpM4 Expression and Activation and Thereby Attenuates BSCB Disruption/Hemorrhage After Spinal Cord Injury in Male Rats

Endocrinology ◽  
2015 ◽  
Vol 156 (5) ◽  
pp. 1838-1850 ◽  
Author(s):  
Jee Y. Lee ◽  
Hae Y. Choi ◽  
Won H. Na ◽  
Bong G. Ju ◽  
Tae Y. Yune
Keyword(s):  
Spinal Cord ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Matrix Metalloprotease ◽  
Sulfonylurea Receptor ◽  
Transient Receptor Potential Melastatin ◽  
Cord Injury ◽  
17Β Estradiol ◽  
Sulfonylurea Receptor 1 ◽  
Transient Receptor

Blood-spinal cord barrier (BSCB) disruption and progressive hemorrhage after spinal cord injury (SCI) lead to secondary injury and the subsequent apoptosis and/or necrosis of neuron and glia, causing permanent neurological deficits. In this study, we examined the effect of 17β-estradiol (E2) on BSCB breakdown and hemorrhage as well as subsequent inflammation after SCI. After a moderate contusion injury at the 9th thoracic segment of spinal cord, E2 (300 μg/kg) was administered by iv injection immediately after SCI, and the same dose of E2 was then administered 6 and 24 hours after injury. Our data show that E2 attenuated BSCB permeability and hemorrhage and reduced the infiltration of neutrophils and macorphages after SCI. Consistent with this finding, the expression of inflammatory mediators was significantly reduced by E2. Furthermore, E2 treatment significantly inhibited the expression of sulfonylurea receptor 1 and transient receptor potential melastatin 4 after injury, which are known to mediate hemorrhage at an early stage after SCI. Moreover, the expression and activation of matrix metalloprotease-9 after injury, which is known to disrupt BSCB, and the degradation of tight junction proteins, such as zona occludens-1 and occludin, were significantly inhibited by E2 treatment. Furthermore, the protective effects of E2 on BSCB disruption and functional improvement were abolished by an estrogen receptor antagonist, ICI 182780 (3 mg/kg). Thus, our study provides evidence that the neuroprotective effect of E2 after SCI is, in part, mediated by inhibiting BSCB disruption and hemorrhage through the down-regulation of sulfonylurea receptor 1/transient receptor potential melastatin 4 and matrix metalloprotease-9, which is dependent on estrogen receptor.

scholarly journals Characterization Of Selective TRPM8 Ligands And Their Structure Activity Response (S.A.R) Relationship

2010 ◽  
Vol 13 (2) ◽  
pp. 242 ◽  
Author(s):  
Muhammad Azhar Sherkheli ◽  
Angela K. Vogt-Eisele ◽  
Daniel Bura ◽  
Leopoldo R. Beltrán Márques ◽  
Günter Gisselmann ◽  
...  
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Parent Compound ◽  
Receptor Potential ◽  
Basic Research ◽  
Fold Increase ◽  
Ring Structure ◽  
Sensory Nerves ◽  
Transient Receptor Potential Melastatin

PURPOSE: Transient receptor potential melastatin-8 (TRPM8) is an ion channel expressed extensively in sensory nerves, human prostate and overexpressed in a variety of cancers including prostate, breast, lung, colon and skin melanomas. It is activated by innoxious cooling and chemical stimuli. TRPM8 activation by cooling or chemical agonists is reported to induce profound analgesia in neuropathic pain conditions. Known TRPM8 agonists like menthol and icilin cross-activate other thermo-TRP channels like TRPV3 and TRPA1 and mutually inhibit TRPM8. This limits the usefulness of menthol and icilin as TRPM8 ligands. Consequently, the identification of selective and potent ligands for TRPM8 is of high relevance both in basic research and for therapeutic applications. In the present investigation, a group of menthol derivates was characterized. These ligands are selective and potent agonists of TRPM8. Interestingly they do not activate other thermo-TRPs like TRPA1, TRPV1, TRPV2, TRPV3 and TRPV4. These ion channels are also nociceptors and target of many inflammatory mediators. METHODS: Investigations were performed in a recombinant system: Xenopus oocytes microinjected with cRNA of gene of interest were superfused with the test substances after initial responses of known standard agonists. Evoked currents were measured by two-electrode voltage clamp technique. RESULTS: The newly characterized ligands possess an up to six-fold higher potency (EC50 in low µM) and an up to two-fold increase in efficacy compared to the parent compound menthol. In addition, it is found that chemical derivatives of menthol like CPS-368, CPS-369, CPS-125, WS-5 and WS-12 are the most selective ligands for TRPM8. The enhanced activity and selectivity seems to be conferred by hexacyclic ring structure present in all ligands as substances like WS-23 which lack this functional group activate TRPM8 with much lower potency (EC50 in mM) and those with pentacyclcic ring structure (furanone compounds) are totally inactive. CONCLUSION: The new substances activate TRPM8 with a higher potency, efficacy and specificity than menthol and will thus be of importance for the development of pharmacological agents suitable for treatment and diagnosis of certain cancers and as analgesics. STATEMENT OF NOVELTY: The new compounds have an unmatched specificity for TRPM8 ion channels with additional display of high potency and efficacy. Thus these substances are better pharmacological tools for TRPM8 characterization then known compounds and it is suggested that these menthol-derivates may serve as model substances for the development of TRPM8 ligands.

scholarly journals Arrow-Shot Injury to Pediatric Spinal Cord

2021 ◽  
Author(s):  
Vijayveer Singh ◽  
Sharad Thanvi
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injuries ◽  
Pediatric Population ◽  
Cervical Region ◽  
Cervical Cord ◽  
Cord Injury ◽  
Dural Suturing ◽  
Stab Injuries ◽  
Early Surgical Intervention

AbstractPenetrating spinal cord injuries (PSCI) in cervical region are extremely rare in pediatric population. Most injuries in pediatric population are accidental due to gunshot or a stab injury with a sharp or pointed object. Gun shots may result into a severe wound which is usually fatal and may result in death, quadriplegia, or serious long-term disability. Stab injuries are less severe and may result in neurological sequalae. In this paper, an unusual case of pediatric arrow shot partial cervical cord injury is reported which was managed by aggressive neurosurgical management. The arrow lodged in the cervical cord was very near to the vertebral artery leading to parapariesis which recovered well without any complications. Diagnostic imaging at admission included radiographs, computed tomography (CT), and CT angiography of the cervical region. The patient underwent early surgical intervention with removal of foreign body from the cord and subsequent dural suturing.

Calcineurin Regulates Synaptic Plasticity and Nociceptive Transmissionat the Spinal Cord Level

2021 ◽  
pp. 107385842110468
Author(s):  
Yuying Huang ◽  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Protein Phosphatase ◽  
Transient Receptor Potential ◽  
Calcineurin Inhibitors ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Negative Feedback Regulation ◽  
Spinal Cord Level ◽  
Calcineurin Activity

Calcineurin, the predominant Ca2+/calmodulin-dependent serine/threonine protein phosphatase (also known as protein phosphatase 2B), is highly expressed in immune T cells and the nervous system, including the dorsal root ganglion and spinal cord. It controls synaptic transmission and plasticity by maintaining the appropriate phosphorylation status of many ion channels present at presynaptic and postsynaptic sites. As such, normal calcineurin activity in neurons and synapses is mainly involved in negative feedback regulation in response to increased neuronal activity and intracellular Ca2+ levels. Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) are widely used as immunosuppressants in tissue and organ transplantation recipients and for treating autoimmune diseases but can cause severe pain in some patients. Furthermore, diminished calcineurin activity at the spinal cord level may play a major role in the transition from acute to chronic neuropathic pain after nerve injury. Restoring calcineurin activity at the spinal cord level produces long-lasting pain relief in animal models of neuropathic pain. In this article, we provide an overview of recent studies on the critical roles of calcineurin in regulating glutamate NMDA and AMPA receptors, voltage-gated Ca2+ channels, potassium channels, and transient receptor potential channels expressed in the spinal dorsal horn and primary sensory neurons.

Activation of SIRT1 by Hyperbaric  Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

2020 ◽  
Author(s):  
Huiqiang Chen ◽  
Mengyu Yao ◽  
Zhibo Li ◽  
Ranran Xing ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Hyperbaric Oxygenation ◽  
Rating Scale ◽  
Motor Dysfunction ◽  
Sprague Dawley ◽  
Inflammatory Cascade ◽  
Locomotor Function ◽  
Cord Injury

Abstract Background: Emerging evidence demonstrated that hyperbaric oxygenation (HBO) therapy improved the locomotor dysfunction following spinal cord injury (SCI). Sirtuin1(SIRT1) has been characterized as neuroprotection in nerve system. However, whether SIRT1 is involved in alleviation of locomotor function by HBO therapy is unclear. Methods: The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms in adult Sprague-Dawley rats. Results: We found that series HBO therapy significantly improved the locomotor dysfunction and ameliorated the decrease mRNA, protein and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection SIRT1 antagonist EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits and SIRT1 activity loss caused by traumatic SCI injury. However, the rats undergone both series HBO therapy and SIRT1 agonist SRT1720 got the higher BBB score than that undergone series HBO treatment only. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with HBO application. Conclusion: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of inflammatory cascade, apoptosis and autophagy, which contributed to the recovery of motor dysfunction. Key words: HBO, SIRT1, motor dysfunction, inflammation, autophagy, apoptosis

Inflammatory Response and Cell Apoptosis are Inhibited by Indirubin-3′-Oxime via PI3K/Akt Pathway in Rat Model of Spinal Cord Injury ​

2020 ◽  
Author(s):  
Yan Zhu ◽  
Lixue Wu ◽  
Qiuxiang Zhou ◽  
Yueyue Yan ◽  
Jinlong Qu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Rat Model ◽  
Serum Levels ◽  
Motor Dysfunction ◽  
Akt Phosphorylation ◽  
Treatment Groups ◽  
Ppar Γ ◽  
Post Surgery ◽  
Cord Injury

Abstract Spinal cord injury (SCI) main cause of motor dysfunction results in loss of feelings partially or completely. The current study investigated indirubin-3′-oxime (IR3O) for treatment of SCI in rat model and evaluated the related mechanism. Rats in model SCI and ID30 groups were subjected to laminectomy at 8th thoracic vertebra level. Vertebral column was secured by clamping T6 and T10 and SCI model was established by dripping a hammer. Treatment groups received 0.25, 0.5, 0.75 and 1.0 mg/kg doses of ID30 daily for 2-weeks post-surgery. Treatment with ID30 effectively improved BBB score in rats with SCI in dose-based manner. Accumulation of water in spinal cord tissues was alleviated significantly on treatment of SCI rats with ID30. ID30 treatment significantly alleviated SCI mediated higher serum levels of TNF-α and cytokines (IL-1β and IL-6) in SCI rats. In ID30 treated SCI rats SOD, CAT and GSH activities were significantly alleviated. The SCI mediated increased cleaved caspase-3 and -9 levels were alleviated by ID30 treatment significantly. Moreover, ID30 treatment suppressed SCI mediated elevation of PGE2, COX‑2 levels and significantly (P<0.05) elevated PPAR-γ expression. The ID30 treatment of SCI rats significantly (P<0.05) elevated PI3K and Akt phosphorylation. Thus, ID30 inhibited edema and improved BBB score in rats with SCI by targeting pro-inflammatory cytokines and oxidative response. Moreover, in SCI rats ID30 treatment down-regulated apoptotic proteins, promoted PPAR-γ activation and elevated PI3K/Akt phosphorylation. Thus, ID30 has potential to be studied further for development of therapeutic strategy for SCI.

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