Moving From an Averaged to Specific View of Spinal Cord Pain Processing Circuits

Neurons in the superficial dorsal horn (SDH) of the spinal cord play a critical role in processing potentially painful or noxious signals from skin, muscle, and viscera. Many acute pain therapies are based on the notion that altering the excitability of SDH neurons can block or gate these signals and reduce pain. This same notion also underlies treatments for certain chronic pain states. Basic scientists are now beginning to identify a number of potential molecular targets for spinal cord–based pain therapies with a focus on ion channels and receptors that can alter neuronal excitability. The current challenge in pain research is to identify which are the most promising targets and how their manipulation alters pain processing. In this review, we propose that our understanding of spinal pain processing mechanisms and translation of these discoveries into pain therapies could be improved by 1) better appreciating and understanding neuronal heterogeneity in the SDH; 2) establishing connectivity patterns among SDH neuron types; and 3) testing and extending findings made in vitro to intact (in vivo) animal models. As this information becomes available, it will be possible to determine the precise distribution of potential therapeutic targets on various SDH neuron types within specific circuits known to be functionally important in spinal pain processing.

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Cytokine and Growth Factor Activation In Vivo and In Vitro after Spinal Cord Injury

Mediators of Inflammation ◽

10.1155/2016/9476020 ◽

2016 ◽

Vol 2016 ◽

pp. 1-21 ◽

Cited By ~ 34

Author(s):

Elisa Garcia ◽

Jorge Aguilar-Cevallos ◽

Raul Silva-Garcia ◽

Antonio Ibarra

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Critical Role ◽

Glutamate Excitotoxicity ◽

Signaling Proteins ◽

Neurodegenerative Process ◽

Cord Injury ◽

Ion Imbalance

Spinal cord injury results in a life-disrupting series of deleterious interconnected mechanisms encompassed by the primary and secondary injury. These events are mediated by the upregulation of genes with roles in inflammation, transcription, and signaling proteins. In particular, cytokines and growth factors are signaling proteins that have important roles in the pathophysiology of SCI. The balance between the proinflammatory and anti-inflammatory effects of these molecules plays a critical role in the progression and outcome of the lesion. The excessive inflammatory Th1 and Th17 phenotypes observed after SCI tilt the scale towards a proinflammatory environment, which exacerbates the deleterious mechanisms present after the injury. These mechanisms include the disruption of the spinal cord blood barrier, edema and ion imbalance, in particular intracellular calcium and sodium concentrations, glutamate excitotoxicity, free radicals, and the inflammatory response contributing to the neurodegenerative process which is characterized by demyelination and apoptosis of neuronal tissue.

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Ventral midline cells are required for the local control of commissural axon guidance in the mouse spinal cord

Development ◽

10.1242/dev.126.16.3649 ◽

1999 ◽

Vol 126 (16) ◽

pp. 3649-3659

Author(s):

M.P. Matise ◽

M. Lustig ◽

T. Sakurai ◽

M. Grumet ◽

A.L. Joyner

Keyword(s):

Spinal Cord ◽

Critical Role ◽

Floor Plate ◽

Posterior Commissure ◽

Ventral Midline ◽

Mouse Spinal Cord ◽

Commissural Axons ◽

Midline Cells

Specialized cells at the midline of the central nervous system have been implicated in controlling axon projections in both invertebrates and vertebrates. To address the requirement for ventral midline cells in providing cues to commissural axons in mice, we have analyzed Gli2 mouse mutants, which lack specifically the floor plate and immediately adjacent interneurons. We show that a Dbx1 enhancer drives tau-lacZ expression in a subpopulation of commissural axons and, using a reporter line generated from this construct, as well as DiI tracing, we find that commissural axons projected to the ventral midline in Gli2(−/−) embryos. Netrin1 mRNA expression was detected in Gli2(−/−) embryos and, although much weaker than in wild-type embryos, was found in a dorsally decreasing gradient. This result demonstrates that while the floor plate can serve as a source of long-range cues for C-axons in vitro, it is not required in vivo for the guidance of commissural axons to the ventral midline in the mouse spinal cord. After reaching the ventral midline, most commissural axons remained clustered in Gli2(−/−) embryos, although some were able to extend longitudinally. Interestingly, some of the longitudinally projecting axons in Gli2(−/−) embryos extended caudally and others rostrally at the ventral midline, in contrast to normal embryos in which virtually all commissural axons turn rostrally after crossing the midline. This finding indicates a critical role for ventral midline cells in regulating the rostral polarity choice made by commissural axons after they cross the midline. In addition, we provide evidence that interactions between commissural axons and floor plate cells are required to modulate the localization of Nr-CAM and TAG-1 proteins on axons at the midline. Finally, we show that the floor plate is not required for the early trajectory of motoneurons or axons of the posterior commissure, whose projections are directed away from the ventral midline in both WT and Gli2(−/−) embryos, although they are less well organized in Gli2(−/−)mutants.

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Distribution of Spinal Sensitization Evoked by Inflammatory Pain Using Local Spinal Cord Glucose Utilization Combined with 3H-Phorbol 12,13-Dibutyrate Binding in Rats

ISRN Pain ◽

10.1155/2013/340167 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5

Author(s):

Yasuda Seiko ◽

Ishikawa Kozo ◽

Matsumoto Yoshihiro ◽

Ariyoshi Toru ◽

Sasaki Hironori ◽

...

Keyword(s):

Spinal Cord ◽

Intracellular Signaling ◽

Neuronal Excitability ◽

Tissue Injury ◽

Mustard Oil ◽

Functional Changes ◽

Spinal Cord Regions ◽

Pdbu Binding

Aims. Hyperalgesia following tissue injury is induced by plasticity in neurotransmission. Few investigators have considered the ascending input which activates the superficial of spinal cord. The aim was to examine neurotransmission and nociceptive processing in the spinal cord after mustard-oil (MO) injection. Both in vitro and in vivo autoradiographs were employed for neuronal activity and transmission in discrete spinal cord regions using the 14C-2-deoxyglucose method and 3H-phorbol 12,13-dibutyrate (3H-PDBu) binding sites. Methods. To quantify the hyperalgesia evoked by MO, the flinching was counted for 60 min after MO (20%, 50 μL) injection in Wistar rats. Simultaneous determination of 14C-2-deoxyglucose and 3H-PDBu binding was used for a direct observation of neuronal/metabolic changes and intracellular signaling in the spinal cord. Results. MO injection evoked an increase in flinching for 60 min. LSCGU significantly increased in the Rexed I-II with 3H-PDBu binding in the ipsilateral side of spinal cord. Discussion. We clearly demonstrated that the hyperalgesia is primarily relevant to increased neuronal activation with PKC activation in the Rexed I-II of the spinal cord. In addition, functional changes such as “neuronal plasticity” may result in increased neuronal excitability and a central sensitization.

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Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing

Journal of Experimental Medicine ◽

10.1084/jem.20061826 ◽

2007 ◽

Vol 204 (2) ◽

pp. 245-252 ◽

Cited By ~ 114

Author(s):

Camilla I. Svensson ◽

Michela Zattoni ◽

Charles N. Serhan

Keyword(s):

Tissue Injury ◽

Spinal Pain ◽

Pain Processing ◽

Lipoxin A4 ◽

Inflammatory Conditions ◽

Extracellular Signal ◽

Inflammatory State

Inflammatory conditions can lead to debilitating and persistent pain. This hyperalgesia reflects sensitization of peripheral terminals and facilitation of pain signaling at the spinal level. Studies of peripheral systems show that tissue injury triggers not only inflammation but also a well-orchestrated series of events that leads to reversal of the inflammatory state. In this regard, lipoxins represent a unique class of lipid mediators that promote resolution of inflammation. The antiinflammatory role of peripheral lipoxins raises the hypothesis that similar neuraxial systems may also down-regulate injury-induced spinal facilitation of pain processing. We report that the lipoxin A4 receptor is expressed on spinal astrocytes both in vivo and in vitro and that spinal delivery of lipoxin A4, as well as stable analogues, attenuates inflammation-induced pain. Furthermore, activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in astrocytes, which has been indicated to play an important role in spinal pain processing, was attenuated in the presence of lipoxins. This linkage opens the possibility that lipoxins regulate spinal nociceptive processing though their actions upon astrocytic activation. Targeting mechanisms that counterregulate the spinal consequences of persistent peripheral inflammation provide a novel endogenous mechanism by which chronic pain may be controlled.

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A Critical Role of Inhibition in Temporal Processing Maturation in the Primary Auditory Cortex

Cerebral Cortex ◽

10.1093/cercor/bhx057 ◽

2017 ◽

Vol 28 (5) ◽

pp. 1610-1624 ◽

Cited By ~ 5

Author(s):

Dongqin Cai ◽

Rongrong Han ◽

Miaomiao Liu ◽

Fenghua Xie ◽

Ling You ◽

...

Keyword(s):

Auditory Cortex ◽

Temporal Processing ◽

Critical Role ◽

Primary Auditory Cortex ◽

Cortical Inhibition ◽

Fast Spiking ◽

Processing Mechanisms

Abstract Faithful representation of sound envelopes in primary auditory cortex (A1) is vital for temporal processing and perception of natural sounds. However, the emergence of cortical temporal processing mechanisms during development remains poorly understood. Although cortical inhibition has been proposed to play an important role in this process, direct in-vivo evidence has been lacking. Using loose-patch recordings in rat A1 immediately after hearing onset, we found that stimulus-following ability in fast-spiking neurons was significantly better than in regular-spiking (RS) neurons. In-vivo whole-cell recordings of RS neurons revealed that inhibition in the developing A1 demonstrated much weaker adaptation to repetitive stimuli than in adult A1. Furthermore, inhibitory synaptic inputs were of longer duration than observed in vitro and in adults. Early in development, overlap of the prolonged inhibition evoked by 2 closely following stimuli disrupted the classical temporal sequence between excitation and inhibition, resulting in slower following capacity. During maturation, inhibitory duration gradually shortened accompanied by an improving temporal following ability of RS neurons. Both inhibitory duration and stimulus-following ability demonstrated exposure-based plasticity. These results demonstrate the role of inhibition in setting the pace for experience-dependent maturation of temporal processing in the auditory cortex.

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Xanthohumol: A Metabolite with Promising Anti-Neoplastic Potential

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210223095021 ◽

2021 ◽

Vol 21 ◽

Author(s):

Hardeep S. Tuli ◽

Vaishali Aggarwal ◽

Gaurav Parashar ◽

Diwakar Aggarwal ◽

Nidarshana C. Parashar ◽

...

Keyword(s):

Synergistic Effects ◽

Cancer Therapies ◽

Cancer Subtypes ◽

Anti Cancer ◽

Challenges And Opportunities ◽

In Vivo Animal Models ◽

Different Dimensions ◽

Made In

: The overwhelming globalburden of cancer has posed numerous challenges and opportunities for developing anti-cancer therapies. Phytochemicalshave emerged as promising synergistic compounds with potential anti-cancer effects to supplement chemo- and immune-therapeutic regimens. Anti cancer synergistic effects have been investigated in the interaction between phytocompounds derived from flavonoids such as quercetin, apigenin, kaempferol, hesperidin, emodin etc., and conventional drugs. Xanthohumol is one of the prenylatedphytoflavonoid that has demonstrated key anti-cancer activities in in vitro (anti proliferation of cancer cell lines) and in vivo(animal models of xenograft tumours)studies, and has been explored from different dimensions for targeting cancer subtypes. In the last decade, xanthohumol has been investigated how it induces the anti-cancer effects at cellular and molecular level.The different signalling cascades and targets of xanthohumolare summarized in thisreview.Overall, this reviewsummarizes the current advances made in the field of natural compounds with special reference to xanthohumol and its promising anti-cancer effectsto inhibit tumour progression.The present review hasalso touched upon the potential of xanthohumol transitioning into a lead candidate from nano-therapy viewpoint along with the challenges which need to be addressed for extensive pre-clinical and clinical anti-cancer studies.

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RNF141 interacts with KRAS to promote colorectal cancer progression

Oncogene ◽

10.1038/s41388-021-01877-4 ◽

2021 ◽

Author(s):

Jiuna Zhang ◽

Xiaoyu Jiang ◽

Jie Yin ◽

Shiying Dou ◽

Xiaoli Xie ◽

...

Keyword(s):

Colorectal Cancer ◽

Plasma Membrane ◽

Tumor Growth ◽

Cancer Progression ◽

Critical Role ◽

Ring Finger ◽

Immunohistochemical Analysis ◽

Bimolecular Fluorescence Complementation

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.

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Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Cancers ◽

10.3390/cancers13040668 ◽

2021 ◽

Vol 13 (4) ◽

pp. 668

Author(s):

Concetta Altamura ◽

Maria Raffaella Greco ◽

Maria Rosaria Carratù ◽

Rosa Angela Cardone ◽

Jean-François Desaphy

Keyword(s):

Ovarian Cancer ◽

Ion Channels ◽

Transient Receptor Potential ◽

Critical Role ◽

Gynecologic Cancer ◽

Receptor Potential ◽

Transient Receptor Potential Channels ◽

Platinum Resistance

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

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Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

Cell Death and Differentiation ◽

10.1038/s41418-020-00685-9 ◽

2021 ◽

Author(s):

Wen-Dai Bao ◽

Pei Pang ◽

Xiao-Ting Zhou ◽

Fan Hu ◽

Wan Xiong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Impairment ◽

Iron Homeostasis ◽

Critical Role ◽

Gene Set Enrichment Analysis ◽

Molecular Characteristics ◽

Intracellular Iron

AbstractIron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

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