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Neuropathic plasticity

Zhi Chai, Cungen Ma, Xiaoming Jin
Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability...
January 2019: Neural Regeneration Research
Krisztina Mekli, Adam Stevens, Alan D Marshall, Thalida E Arpawong, Drystan F Phillips, Gindo Tampubolon, Jinkook Lee, Carol A Prescott, James Y Nazroo, Neil Pendleton
The concept of frailty has been used in the clinical and research field for more than two decades. It is usually described as a clinical state of heightened vulnerability to poor resolution of homeostasis after a stressor event, which thereby increases the risk of adverse outcomes, including falls, delirium, disability and mortality. Here we report the results of the first genome-wide association scan and comparative gene ontology analyses where we aimed to identify genes and pathways associated with the deficit model of frailty...
2018: PloS One
Salim Megat, Pradipta R Ray, Jamie K Moy, Tzu-Fang Lou, Paulino Barragan-Iglesias, Yan Li, Grishma Pradhan, Andi Wanghzou, Ayesha Ahmad, Michael D Burton, Robert Y North, Patrick M Dougherty, Arkady Khoutorsky, Nahum Sonenberg, Kevin R Webster, Gregory Dussor, Zachary T Campbell, Theodore J Price
Nociceptors, sensory neurons in the dorsal root ganglion (DRG) that detect damaging or potentially damaging stimuli, are key drivers of neuropathic pain. Injury to these neurons causes activation of translation regulation signaling including the mechanistic target of rapamycin complex 1 (mTORC1) and mitogen activated protein kinase interacting kinase (MNK) eukaryotic initiation factor (eIF) 4E pathways. This is a mechanism driving changes in excitability of nociceptors that is critical for the generation of chronic pain states, however, the mRNAs that are translated to lead to this plasticity have not been elucidated...
November 20, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Youfang Chen, Shao-Rui Chen, Hong Chen, Jixiang Zhang, Hui-Lin Pan
Painful peripheral neuropathy is a severe and difficult-to-treat neurological complication associated with cancer chemotherapy. Although chemotherapeutic drugs such as paclitaxel are known to cause tonic activation of presynaptic NMDA receptors (NMDARs) to potentiate nociceptive input, the molecular mechanism involved in this effect is unclear. α2δ-1, commonly known as a voltage-activated calcium channel subunit, is a newly discovered NMDAR-interacting protein and plays a critical role in NMDAR-mediated synaptic plasticity...
November 15, 2018: Journal of Neurochemistry
Sanne Kikkert, Melvin Mezue, Jacinta O'Shea, David Henderson-Slater, Heidi Johansen-Berg, Irene Tracey, Tamar R Makin
OBJECTIVE: Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP-related disease mechanisms. Non-invasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. While NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS-induced PLP relief is needed for future implementation of such treatment and generalisation to related conditions...
November 1, 2018: Annals of Neurology
Daniela Regina Brandao Tavares, Jane Erika Frazao Okazaki, Aline Pereira Rocha, Marcia Valeria De Andrade Santana, Ana Carolina Pereira Nunes Pinto, Vinicius Tassoni Civile, Fania Cristina Santos, Felipe Fregni, Virginia Fernandes Moça Trevisani
BACKGROUND: Knee osteoarthritis (OA) has been the main cause behind chronic pain and disabilities in the elderly population. The traditional treatment for knee OA pain currently concerns a number of combinations of pharmacological and nonpharmacological therapies. However, such combinations have displayed little effects on a significant group of subjects. In addition to this, pharmacological treatments often cause adverse effects, which limits their use on this population. Previous studies showed that chronic knee OA pain may be associated with maladaptive compensatory plasticity in pain-related neural central circuits indexed by a defective descending pain-inhibitory system...
October 29, 2018: JMIR Research Protocols
Yuhua Yin, Min-Hee Yi, Dong Woon Kim
Neuropathic pain (NP) is caused by lesions of the peripheral fibers and central neurons in the somatosensory nervous system and affects 7-10% of the general population. Although the distinct cause of neuropathic pain has been investigated in primary afferent neurons over the years, pain modulation by central sensitization remains controversial. NP is believed to be driven by cell type-specific spinal synaptic plasticity in the dorsal horn. Upon intense afferent stimulation, spinothalamic tract neurons are potentiated, whereas GABAergic interneurons are inhibited leading to long-term depression...
2018: Pain Research & Management: the Journal of the Canadian Pain Society
Cristina Alba-Delgado, Sarah Mountadem, Noémie Mermet-Joret, Lénaïc Monconduit, Radhouane Dallel, Alain Artola, Myriam Antri
Mechanical allodynia, a widespread pain symptom which still lacks effective therapy, is associated with the activation of a dorsally-directed polysynaptic circuit within spinal (SDH) or medullary dorsal horn (MDH), whereby tactile inputs into deep SDH/MDH can gain access to superficial SDH/MDH, eliciting pain. Inner lamina II (IIi ) interneurons expressing the γ isoform of protein kinase C (PKCγ+ ) are key elements for allodynia circuits but how they operate is still unclear. Combining behavioral, ex vivo electrophysiological and morphological approaches in an adult rat model of facial inflammatory pain (Complete Freund's Adjuvant, CFA), we show that the mechanical allodynia observed 1h after CFA injection is associated with i) sensitization (using ERK1/2 phosphorylation as a marker) and ii) reduced dendritic arborizations and enhanced spine density-in exclusively PKCγ+ interneurons, but iii) depolarized resting membrane potential (RMP) in all lamina IIi PKCγ+ /PKCγ- interneurons...
October 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Georgios Baskozos, John M Dawes, Jean S Austin, Ana Antunes-Martins, Lucy McDermott, Alex J Clark, Teodora Trendafilova, Jon G Lees, Stephen B McMahon, Jeffrey S Mogil, Christine Orengo, David L Bennett
Dorsal root ganglion (DRG) neurons provide connectivity between peripheral tissues and spinal cord. Transcriptional plasticity within DRG sensory neurons after peripheral nerve injury contributes to nerve repair but also leads to maladaptive plasticity, including the development of neuropathic pain. This study presents tissue and neuron specific expression profiling of both known and novel Long Non-Coding RNAs (LncRNAs) in rodent DRG following nerve injury. We have identified a large number of novel LncRNAs expressed within rodent DRG, a minority of which were syntenically conserved between mouse, rat and human and which including both- intergenic and antisense LncRNAs...
October 16, 2018: Pain
Yong Fang Zhu, Jacek M Kwiecien, Wojciech Dabrowski, Robert Ungard, Kan Lun Zhu, Jan D Huizinga, James L Henry, Gurmit Singh
Evidence suggests that there are both nociceptive and neuropathic components of cancer-induced pain. We have observed that changes in intrinsic membrane properties and excitability of normally non-nociceptive Aβ sensory neurons are consistent in rat models of peripheral neuropathic pain and cancer-induced pain. This has prompted a comparative investigation of the intracellular electrophysiological characteristics of sensory neurons and of the ultrastructural morphology of the dorsal horn in rat models of neuropathic pain and cancer-induced pain...
January 2018: Molecular Pain
X Moisset, J-P Lefaucheur
The use of medications in chronic neuropathic pain may be limited with regard to efficacy and tolerance. Therefore, non-pharmacological approaches, using electrical stimulation of the cortex has been proposed as an alternative. First, in the early nineties, surgically-implanted epidural motor cortex stimulation (EMCS) was proven to be effective to relieve refractory neuropathic pain. Later, non-invasive stimulation techniques were found to produce similar analgesic effects, at least by means of repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1)...
October 12, 2018: Revue Neurologique
Ken-Ichiro Hayashida, James C Eisenach
Gabapentinoids are effective in a wide range of animal pain models and in patients with neuropathic pain and has become one of first-line treatments for neuropathic pain. Because spinal plasticity and sensitization have been intensely studied in neuropathic pain, most laboratory studies have focused on actions of gabapentinoids in the spinal cord, where they reduce primary afferent traffic and excitation of spinal nociceptive neurons, via interaction with α2δ subunits of voltage-gated Ca2+ channels. However, a recent clinical study questioned the relevance of this in vitro and in vivo rodent studies by demonstrating a complete lack of clinical efficacy of intrathecal gabapentin in patients with chronic pain...
2018: Advances in Experimental Medicine and Biology
Tzu-Hao Harry Chao, Jyh-Horng Chen, Chen-Tung Yen
Neuropathic pain is a major worldwide health problem. Although central sensitization has been reported in well-established neuropathic conditions, information on the acute brain activation patterns in response to peripheral nerve injury is lacking. This study first mapped the brain activity in rats immediately following spared nerve injury (SNI) of the sciatic nerve. Using blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD-fMRI), we observed sustained activation in the bilateral insular cortices (ICs), primary somatosensory cortex (S1), and cingulate cortex...
October 1, 2018: Molecular Brain
Serena Boccella, Claudia Cristiano, Rosaria Romano, Monica Iannotta, Carmela Belardo, Antonio Farina, Francesca Guida, Fabiana Piscitelli, Enza Palazzo, Mariacristina Mazzitelli, Roberta Imperatore, Lea Tunisi, Vito de Novellis, Luigia Cristino, Vincenzo Di Marzo, Antonio Calignano, Sabatino Maione, Livio Luongo
Chronic pain is associated with cognitive deficits. Palmitoylethanolamide (PEA) has been shown to ameliorate pain and pain-related cognitive impairments by restoring glutamatergic synapses functioning in the spared nerve injury (SNI) of the sciatic nerve in mice. SNI reduced mechanical and thermal threshold, spatial memory and LTP at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway. It decreased also postsynaptic density, volume and dendrite arborization of DG and increased the expression of metabotropic glutamate receptor 1 and 7 (mGluR1 and mGluR7), of the GluR1, GluR1s845 and GluR1s831 subunits of AMPA receptor and the levels of glutamate in the DG...
September 25, 2018: Neurobiology of Disease
Kohei Matsubayashi, Narihito Nagoshi, Yuji Komaki, Kota Kojima, Munehisa Shinozaki, Osahiko Tsuji, Akio Iwanami, Ryosuke Ishihara, Norio Takata, Morio Matsumoto, Masaru Mimura, Hideyuki Okano, Masaya Nakamura
Neural connectivity has recently been shown to be altered after spinal cord injury (SCI) not only in the spinal cord but also in the brain. However, to date, no studies have analyzed the functional alterations after SCI in various areas of the cerebral cortex over time. To examine the plasticity of the neural connectivity in the brain after SCI, we performed resting-state functional magnetic resonance imaging (rs-fMRI) in awake adult mice pre- and post-SCI. After a complete thoracic SCI, the functional connectivity between the primary motor (MOp) and primary sensory (SSp) areas was significantly decreased during the chronic phase...
September 26, 2018: Scientific Reports
Max Ortiz-Catalan
Phantom limb pain (PLP) is a debilitating condition common after amputation that can considerably hinder patients' quality of life. Several treatments have reported promising results in alleviating PLP. However, clinical evaluations are usually performed in small cohorts and rigorous clinical trials are scarce. In addition, the underlying mechanisms by which novel interventions alleviate PLP are often unclear, potentially because the condition itself is poorly understood. This article presents a theoretical framework of PLP that can be used as groundwork for hypotheses of novel treatments...
2018: Frontiers in Neurology
Yu Zhao, Zhanyun Yang
Neuropathic pain (NP) is a common clinical chronic pain with very complex mechanisms. This study explored the function of activated Wnt signaling pathway in NP. A rat model of chronic constriction injury (CCI) was established. Different doses of IWP-2, a Wnt signal inhibitor, were intrathecally injected to observe the behavior indicators at different time-points, including the pain induced by mechanical stimulation and thermal stimulation. The mRNA and protein levels of Wnt-3a, Frizzled 4 and β-catenin in lumbar (L) 4-6 dorsal root ganglion (DRG) of rats in each group, as well as synaptic plasticity-related molecules in DRG region of rats were detected by RT-PCR and western blotting, respectively...
October 2018: Experimental and Therapeutic Medicine
Xingrui Gong, Yongmei Chen, Jing Chang, Yue Huang, Meihau Cai, Mazhong Zhang
BACKGROUND: Infant nerve injury causes delayed adolescent neuropathic pain, but whether it also leads to psychiatric illness is unknown. Environmental enrichment (EE) increases social communication and activity. Thus, our goal was to test anxiety- and depression-like behaviors after infant peripheral nerve injury and evaluate the effect of environmental enrichment on these models of affective disorders. METHODS: Open field, elevated plus maze, sucrose preference, and pain behaviors (paw withdrawal threshold, spontaneous guarding score, and cold response to acetone) were measured in rats that received infant spared nerve injury (SNI)...
September 12, 2018: Journal of Neuroinflammation
Yu-Chia Chuang, Cheng-Han Lee, Wei-Hsin Sun, Chih-Cheng Chen
Advillin is a sensory neuron-specific actin-binding protein expressed at high levels in all types of somatosensory neurons in early development. However, the precise role of advillin in adulthood is largely unknown. Here we reveal advillin expression restricted to isolectin B4-positive (IB4+ ) neurons in the adult dorsal root ganglia (DRG). Advillin knockout (KO) specifically impaired axonal regeneration in adult IB4+ DRG neurons. During axon regeneration, advillin was expressed at the very tips of filopodia and modulated growth cone formation by interacting with and regulating focal-adhesion-related proteins...
September 4, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mohammed Zacky Ariffin, Khairunisa Mohamad Ibrahim, Andy Thiam-Huat Lee, Rui Zhi Lee, Shou Yu Poon, Hwai Kit Thong, Eugene Hern Choon Liu, Chian-Ming Low, Sanjay Khanna
The present study explored the role of the medial septal region (MS) in experimental neuropathic pain. For the first time, we found that the MS sustains nociceptive behaviors in rodent models of neuropathic pain, especially in the chronic constriction injury (CCI) model and the paclitaxel model of chemotherapy-induced neuropathic pain. For example, inactivation of the MS with intraseptal muscimol (2 μg/μl, 0.5 μl), a GABA mimetic, reversed peripheral hypersensitivity (PH) in the CCI model and induced place preference in a conditioned place preference task, a surrogate measure of spontaneous nociception...
August 8, 2018: Scientific Reports
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