Peripheral Nerve Injury Modulates Neurotrophin Signaling in the Peripheral and Central Nervous System

2014 ◽  
Vol 50 (3) ◽  
pp. 945-970 ◽  
Author(s):  
Mette Richner ◽  
Maj Ulrichsen ◽  
Siri Lander Elmegaard ◽  
Ruthe Dieu ◽  
Lone Tjener Pallesen ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Neurotrophin Signaling

scholarly journals Spinal Microglial and Perivascular Cell Cannabinoid Receptor Type 2 Activation Reduces Behavioral Hypersensitivity without Tolerance after Peripheral Nerve Injury

2008 ◽  
Vol 108 (4) ◽  
pp. 722-734 ◽  
Author(s):  
Alfonso Romero-Sandoval ◽  
Nancy Nutile-McMenemy ◽  
Joyce A. DeLeo
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Side Effects ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Cannabinoid Receptor ◽  
Nerve Transection ◽  
Cd163 Expression ◽  
Antinociceptive Tolerance

Background Cannabinoids induce analgesia by acting on cannabinoid receptor (CBR) types 1 and/or 2. However, central nervous system side effects and antinociceptive tolerance from CBR1 limit their clinical use. CBR2 exist on spinal glia and perivascular cells, suggesting an immunoregulatory role of these receptors in the central nervous system. Previously, the authors showed that spinal CBR2 activation reduces paw incision hypersensitivity and glial activation. This study tested whether CBR2 are expressed in glia and whether their activation would induce antinociception, glial inhibition, central side effects, and antinociceptive tolerance in a neuropathic rodent pain model. Methods Rats underwent L5 spinal nerve transection or sham surgery, and CBR2 expression and cell localization were assessed by immunohistochemistry. Animals received intrathecal injections of CBR agonists and antagonists, and mechanical withdrawal thresholds and behavioral side effects were assessed. Results Peripheral nerve transection induced hypersensitivity, increased expression of CR3/CD11b and CBR2, and reduced ED2/CD163 expression in the spinal cord. The CBR2 were localized to microglia and perivascular cells. Intrathecal JWH015 reduced peripheral nerve injury hypersensitivity and CR3/CD11b expression and increased ED2/CD163 expression in a dose-dependent fashion. These effects were prevented by intrathecal administration of the CBR2 antagonist (AM630) but not the CBR1 antagonist (AM281). JWH015 did not cause behavioral side effects. Chronic intrathecal JWH015 treatment did not induce antinociceptive tolerance. Conclusions These data indicate that intrathecal CBR2 agonists may provide analgesia by modulating the spinal immune response and microglial function in chronic pain conditions without inducing tolerance and neurologic side effects.

scholarly journals Role of the immune system in neuropathic pain

2019 ◽  
Vol 20 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Marzia Malcangio
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Immune System ◽  
Peripheral Nerve ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Immune Cells ◽  
Peripheral Nerve Injury

AbstractBackgroundAcute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).Critical role for immune system cells in chronic painPreclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.Immune system reactions to peripheral nerve injuriesAt the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.Immune system mechanisms in the central nervous systemIn the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.Conclusions and implicationsDefinition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.

scholarly journals Underlying histopathology of peripheral nerve injury and the classical nerve repair techniques

2019 ◽  
pp. 17-22
Author(s):  
Marin Andrei ◽  
Mihai Ruxandra Ioana ◽  
Enescu Dan Mircea
Keyword(s):  
Nervous System ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Nerve Repair ◽  
Experimental Studies ◽  
Key Factors ◽  
Regeneration Rate ◽  
The Central Nervous System

A much-debated subject in the last 20 years, the recovery after peripheral nerve injury still remains one of the most researched themes of our days. Although the central nervous system has not exhibited any ground-breaking discoveries in matters of healing through surgical procedures, this is not the case for the peripheral nervous system (PNS). The PNS recovery after injury has improved over the years so we now speak of time and percentage of rehabilitation. The increased interest for this subject is a result in the development of the medical technique, that allowed the creation of new molecules capable to improve the regeneration rate. Furthermore, the evolution in diagnostic parameters, as well as the possibility of a thorough follow-up, contributed to the ascending research of this field.  One must not forget that all experimental studies have as endpoint obtaining safe and reproducible solutions which can be applied in treating patients with peripheral nerve injury. We will briefly present the microscopic events that occur following a peripheral nerve injury, the key factors which influence their regeneration as well as the classical techniques used to repair them. However, the most intriguing topic in nerve regeneration is not related to the surgical procedure (considered to be the Gold Standard in whole nerve injury), but rather the helping substances that facilitate a faster and better recovery.

scholarly journals Using Stem Cells to Grow Artificial Tissue for Peripheral Nerve Repair

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Kulraj Singh Bhangra ◽  
Francesca Busuttil ◽  
James B. Phillips ◽  
Ahad A. Rahim
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Nervous System ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Nerve Repair ◽  
Cell Types ◽  
Neural Lineage ◽  
Essential Resource

Peripheral nerve injury continues to pose a clinical hurdle despite its frequency and advances in treatment. Unlike the central nervous system, neurons of the peripheral nervous system have a greater ability to regenerate. However, due to a number of confounding factors, this is often both incomplete and inadequate. The lack of supportive Schwann cells or their inability to maintain a regenerative phenotype is a major factor. Advances in nervous system tissue engineering technology have led to efforts to build Schwann cell scaffolds to overcome this and enhance the regenerative capacity of neurons following injury. Stem cells that can differentiate along a neural lineage represent an essential resource and starting material for this process. In this review, we discuss the different stem cell types that are showing promise for nervous system tissue engineering in the context of peripheral nerve injury. We also discuss some of the biological, practical, ethical, and commercial considerations in using these different stem cells for future clinical application.

scholarly journals Enhanced Pain Sensitivity with Systemic Ultrastructural Changes of the Nervous Systems after Cobra Venom Injection is Reversed by Electroacupuncture Treatment

2018 ◽  
Vol 1 (21;1) ◽  
pp. E509-E521
Author(s):  
Jian-xiong An
Keyword(s):  
Nervous System ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Pain Sensitivity ◽  
Local Injection ◽  
Cobra Venom ◽  
Ultrastructural Changes ◽  
Light Microscope Level

Background: Electroacupuncture (EA) has been proved to be effective in treating certain neuropathic pain conditions. The mechanisms of pain relief by EA are not fully understood. There have been sporadic reports of damage in the peripheral nervous system (PNS) and regions of the central nervous system (CNS) at the ultrastructural level following peripheral nerve injury. However, information about possible systemic changes in the PNS and CNS after nerve injury is scarce. Objectives: The goal of this study was to examine the ultrastructural changes of the nervous system induced by a local injection of cobra venom into the sciatic nerve and to compare the ultrastructural changes in rats with or without treatment with EA or pregabalin. Study Design: An experimental study. Setting: Department of Anesthesiology, Pain Medicine, and Critical Care Medicine, Aviation General Hospital of China Medical University. Methods: In this study, using an established model of sciatic neuralgia induced by local injection of cobra venom into the sciatic nerve, we examined ultrastructural changes of the PNS and CNS and how they respond to EA and pregabalin treatment. EA and pregabalin were given daily from postoperative day (POD) 14 to 36. Based on previous works, the frequency of EA stimulation of the ST36 and GB34 acupoints was held to 2/100 Hz variable. Pain sensitivity in the sciatic neuralgia rats with and without treatments was assessed using the von Frey test. Ultrastructural alterations were examined bilaterally in the prefrontal cortex, hippocampus, medulla oblongata; and the cervical, thoracic, and lumbar spinal cords on PODs 14, 40, and 60. Ultrastructural examinations were also carried out on the bilateral sciatic nerves and dorsal root ganglion (DRG) at the cervical, thoracic and lumbar levels. In rats treated with EA or pregabalin, the ultrastructure was examined on PODs 40 and 60. Results: Behavioral signs of pain and systemic ultrastructural changes including demyelination were observed at all levels of the PNS and CNS in rats with sciatic neuralgia. After intervention, the mechanical withdrawal thresholds of the EA group and pregabalin group were significantly higher than that of the cobra venom group (P < 0.05). Both EA and pregabalin treatments partially reversed increased cutaneous sensitivity to mechanical stimulation. However, only the EA treatment was able to repair the ultrastructural damages caused by cobra venom. Limitations: The results confirm that peripheral nerve injury led to the ultrastructural damage at different levels of the CNS as demonstrated with electron microscopy; however, we need to further verify this at both the molecular level and in light microscope level. Sciatic neuralgia induced by cobra venom is a chemical injury, and whether this exactly mimics a peripheral nerve mechanical injury is still unclear. Conclusions: Local cobra venom injection leads to systemic neurotoxicity. EA and pregabalin alleviate pain via different mechanisms. Key words: Sciatic neuralgia, cobra venom, demyelination, electroacupuncture, pregabalin, rat model

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