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Neuropathic plasticity

Anna Tyrtyshnaia, Igor Manzhulo, Yulia Kipryushina, Ekaterina Ermolenko
Neuropathic pain is a condition characterized by unpleasant sensory and emotional experiences associated with a number of diseases or injuries affecting the sensory system through various mechanisms. In this study, we focused on the impact of chronic neuropathic pain on the microglial state and hippocampal neurogenesis in aged mice. In addition, we examined the effects of alkyl glycerol ethers (AGE) treatment on behavioral parameters, hippocampal neuronal and microglial plasticity in aged C57BL/6 mice with neuropathic pain...
March 21, 2019: International Journal of Molecular Medicine
Robert Y North, Yan Li, Pradipta Ray, Laurence D Rhines, Claudio Esteves Tatsui, Ganesh Rao, Caj A Johansson, Hongmei Zhang, Yeun Hee Kim, Bo Zhang, Gregory Dussor, Tae Hoon Kim, Theodore J Price, Patrick M Dougherty
Neuropathic pain encompasses a diverse array of clinical entities affecting 7-10% of the population, which is challenging to adequately treat. Several promising therapeutics derived from molecular discoveries in animal models of neuropathic pain have failed to translate following unsuccessful clinical trials suggesting the possibility of important cellular-level and molecular differences between animals and humans. Establishing the extent of potential differences between laboratory animals and humans, through direct study of human tissues and/or cells, is likely important in facilitating translation of preclinical discoveries to meaningful treatments...
March 19, 2019: Brain: a Journal of Neurology
Anton Rogachov, Anuj Bhatia, Joshua C Cheng, Rachael L Bosma, Junseok A Kim, Natalie R Osborne, Kasey S Hemington, Lakshmikumar Venkatraghavan, Karen D Davis
Therapeutic interventions for neuropathic pain (NP), such as the NMDA-antagonist ketamine, can vary widely in effectiveness; Here, we conducted a longitudinal functional MRI study to test the hypothesis that the pain relieving effect of ketamine is due to reversal of abnormalities in regional low frequency brain oscillations (LFOs) and abnormal cross-network functional connectivity (FC) of the dynamic pain connectome. We found that: 1) ketamine decreased regional LFOs in the posterior cingulate cortex (PCC) of the default mode network (DMN), 2) a machine learning algorithm demonstrated that treatment-induced brain changes could be used to make generalizable inferences about pain relief, 3) treatment responders exhibited a significant decrease in cross-network static FC between the PCC and regions of the sensorimotor (SM) and salience networks following treatment, 4) the degree of reduced cross-network FC was correlated with the amount of pain relief, and 5) ketamine treatment did not produce significant differences in static or dynamic FC within the ascending nociceptive- or descending antinociceptive pathway...
March 4, 2019: Pain
Nannan Li, Chunmei Li, Rui Han, Yu Wang, Mina Yang, Hongbo Wang, Jingwei Tian
Background and Purpose: Sedation and somnolence remain serious adverse effects of the existing analgesics (e.g., pregabalin, duloxetine) for neuropathic pain. The available evidence indicates that serotonin (5-HT), noradrenaline (NE), and dopamine (DA) play important roles in modulating the descending inhibitory pain pathway and sleep-wake cycle. The aim of this work was to test the hypothesis that LPM580098, a novel triple reuptake inhibitor (TRI) of 5-HT, NE, and DA, has analgesic effect, and does not induce significant adverse effects associated with central inhibition, such as sedation and somnolence...
2019: Frontiers in Pharmacology
Meichun Deng, Shao-Rui Chen, Hui-Lin Pan
Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission...
February 20, 2019: Cellular and Molecular Life Sciences: CMLS
Víctor M López-Álvarez, Stefano Cobianchi, Xavier Navarro
OBJECTIVES: We aimed to investigate if different protocols of electrical stimulation following nerve injury might improve neuropathic pain outcomes and modify associated plastic changes at the spinal cord level. MATERIALS AND METHODS: Adult rats were subjected to sciatic nerve transection and repair, and distributed in four groups: untreated (SNTR, n = 12), repeated acute electrical stimulation (rAES, 50 Hz, one hour, n = 12), chronic electrical stimulation (CES, 50 Hz, one hour, n = 12), and increasing-frequency chronic electrical stimulation (iCES, one hour, n = 12) delivered during two weeks following the lesion...
February 20, 2019: Neuromodulation: Journal of the International Neuromodulation Society
Diana N J Lockwood
The chronic aspects of leprosy are discussed here. They are a consequence of the peripheral nerve damage that affects many patients during their lifetime with leprosy. The peripheral nerve damage leaves people unable to feel and with weakness in their hands and feet. They are at risk of damaging their hands and feet, causing the disabilities and deformities that characterise late leprosy.More than 200 000 new leprosy patients are diagnosed globally each year. Better data are needed from cohort studies to estimate the number of patients developing nerve damage and modelling studies are needed to estimate the number of patients who develop disabilities...
January 31, 2019: Transactions of the Royal Society of Tropical Medicine and Hygiene
Satoshi Fujita, Kiyofumi Yamamoto, Masayuki Kobayashi
The primary sensory cortex processes competitive sensory inputs. Ablation of these competitive inputs induces neuroplastic changes in local cortical circuits. However, information concerning cortical plasticity induced by a disturbance of competitive nociceptive inputs is limited. Nociceptive information from the maxillary and mandibular molar pulps converges at the border between the ventral secondary somatosensory cortex (S2) and insular oral region (IOR); therefore, S2/IOR is a suitable target for examining the cortical changes induced by a disturbance of noxious inputs, which often causes neuropathic pain and allodynia...
January 2019: ENeuro
Zongqin Zhang, Xiaobao Ding, Zhiwei Zhou, Zhuang Qiu, Naihao Shi, Shasha Zhou, Lei Du, Xia Zhu, Yuqing Wu, Xiaoxing Yin, Chenghua Zhou
Accumulating evidence has demonstrated that the enhanced synaptic plasticity of nociceptive interneurons in the spinal dorsal horn is the basis of central sensitization in neuropathic pain. Our previous results demonstrate that Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, alleviates neuropathic pain in type 2 diabetes mellitus (T2DM) rats. SIRT1 has also been reported to regulate synaptic plasticity in different brain neurons. However, the role of SIRT1 in synaptic plasticity of spinal dorsal horn neurons remains unknown...
January 11, 2019: Pain
Dinesh Selvarajah, Iain D Wilkinson, Fang Fang, Adithya Sankar, Jennifer Davies, Elaine Boland, Joseph Harding BMedSci, Ganesh Rao, Rajiv Gandhi, Irene Tracey, Solomon Tesfaye
Diabetic distal symmetrical peripheral polyneuropathy (DSP) results in decreased somatosensory cortical gray matter volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has examined whether changes in brain volume alters the functional organisation of the somatosensory cortex and how this relates to the different painful DSP clinical phenotypes. In this case-controlled, multimodal magnetic resonance brain imaging study of 44 carefully phenotyped subjects, we found significant anatomical and functional changes in the somatosensory cortex...
January 7, 2019: Diabetes
Gang Chen, Yu-Qiu Zhang, Yawar J Qadri, Charles N Serhan, Ru-Rong Ji
The previous decade has seen a rapid increase in microglial studies on pain, with a unique focus on microgliosis in the spinal cord after nerve injury and neuropathic pain. Numerous signaling molecules are altered in microglia and contribute to the pathogenesis of pain. Here, we discuss how microglial signaling regulates spinal cord synaptic plasticity in acute and chronic pain conditions with different degrees and variations of microgliosis. We highlight that microglial mediators such as pro- and anti-inflammatory cytokines are powerful neuromodulators that regulate synaptic transmission and pain via neuron-glial interactions...
December 19, 2018: Neuron
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
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