Purpose of Review
Our goal is to examine the processes—both central and peripheral—that underlie the development of peripherally-induced neuropathic pain (pNP) and to highlight recent evidence for ...mechanisms contributing to its maintenance. While many pNP conditions are initiated by damage to the peripheral nervous system (PNS), their persistence appears to rely on maladaptive processes within the central nervous system (CNS). The potential existence of an autonomous pain-generating mechanism in the CNS creates significant implications for the development of new neuropathic pain treatments; thus, work towards its resolution is crucial. Here, we seek to identify evidence for PNS and CNS independently generating neuropathic pain signals.
Recent Findings
Recent preclinical studies in pNP support and provide key details concerning the role of multiple mechanisms leading to fiber hyperexcitability and sustained electrical discharge to the CNS. In studies regarding central mechanisms, new preclinical evidence includes the mapping of novel inhibitory circuitry and identification of the molecular basis of microglia-neuron crosstalk. Recent clinical evidence demonstrates the essential role of peripheral mechanisms, mostly via studies that block the initially damaged peripheral circuitry. Clinical central mechanism studies use imaging to identify potentially self-sustaining infra-slow CNS oscillatory activity that may be unique to pNP patients.
Summary
While new preclinical evidence supports and expands upon the key role of central mechanisms in neuropathic pain, clinical evidence for an autonomous central mechanism remains relatively limited. Recent findings from both preclinical and clinical studies recapitulate the critical contribution of peripheral input to maintenance of neuropathic pain. Further clinical investigations on the possibility of standalone central contributions to pNP may be assisted by a reconsideration of the agreed terms or criteria for diagnosing the presence of central sensitization in humans.
Department of Neurobiology, Physiology, and Behavior, College of Biological Sciences and Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, California
...The intrinsic electrical properties and the synaptic input-output relationships of neurons are governed by the action of voltage-dependent ion channels. The localization of specific populations of ion channels with distinct functional properties at discrete sites in neurons dramatically impacts excitability and synaptic transmission. Molecular cloning studies have revealed a large family of genes encoding voltage-dependent ion channel principal and auxiliary subunits, most of which are expressed in mammalian central neurons. Much recent effort has focused on determining which of these subunits coassemble into native neuronal channel complexes, and the cellular and subcellular distributions of these complexes, as a crucial step in understanding the contribution of these channels to specific aspects of neuronal function. Here we review progress made on recent studies aimed to determine the cellular and subcellular distribution of specific ion channel subunits in mammalian brain neurons using in situ hybridization and immunohistochemistry. We also discuss the repertoire of ion channel subunits in specific neuronal compartments and implications for neuronal physiology. Finally, we discuss the emerging mechanisms for determining the discrete subcellular distributions observed for many neuronal ion channels.
Soil is the basis of all agroecosystem and its health is of utmost importance for the better productivity and sustainability of agriculture but soil health is constantly deteriorating due to the ...addition of xenobiotic compounds by various agronomicals and industrial applications. Pesticides are widely used throughout the world for controlling the spread of various pests in agroecosystem but the persistent nature and non-targeted toxicity of the compounds have also become the major concern for agroecosystem and is directly hampering the yield of agricultural produce. Hence, removal of these substances is of utmost importance and a variety of approaches are in progress. Currently, the use of biological resources for the removal and degradation of these substances has emerged as a powerful tool. Numerous bacterial and fungal species with degradation ability have been tried and established but very few attempts are made to make a comprehensive evaluation of the potential of these agents. This review thrusts on the bioremediation efficiency of soil fungi with an aim to make a comparative analysis and to critically evaluate their potential application in the field. The species of Aspergillus, Allescheriella, Alternaria, Microsporum, Penicillium, Phlebia, Paecilomyces, Trichoderma, etc. are known for their bioremediation potential. But Aspergillus species are the most widely used for degrading almost all types of pesticides.
Aquaculture is emerging as one of the most viable and promising enterprises for keeping pace with the surging need for animal protein, providing nutritional and food security to humans, particularly ...those residing in regions where livestock is relatively scarce. With every step toward intensification of aquaculture practices, there is an increase in the stress level in the animal as well as the environment. Hence, disease outbreak is being increasingly recognized as one of the most important constraints to aquaculture production in many countries, including India. Conventionally, the disease control in aquaculture has relied on the use of chemical compounds and antibiotics. The development of non-antibiotic and environmentally friendly agents is one of the key factors for health management in aquaculture. Consequently, with the emerging need for environmentally friendly aquaculture, the use of alternatives to antibiotic growth promoters in fish nutrition is now widely accepted. In recent years, probiotics have taken center stage and are being used as an unconventional approach that has numerous beneficial effects in fish and shellfish culture: improved activity of gastrointestinal microbiota and enhanced immune status, disease resistance, survival, feed utilization and growth performance. As natural products, probiotics have much potential to increase the efficiency and sustainability of aquaculture production. Therefore, comprehensive research to fully characterize the intestinal microbiota of prominent fish species, mechanisms of action of probiotics and their effects on the intestinal ecosystem, immunity, fish health and performance is reasonable. This review highlights the classifications and applications of probiotics in aquaculture. The review also summarizes the advancement and research highlights of the probiotic status and mode of action, which are of great significance from an ecofriendly, sustainable, intensive aquaculture point of view.
Microarray gene expression based medical data classification has remained as one of the most challenging research areas in the field of bioinformatics, machine learning and pattern classification. ...This paper proposes two variations of kernel ridge regression (KRR), namely wavelet kernel ridge regression (WKRR) and radial basis kernel ridge regression (RKRR) for classification of microarray medical datasets. Microarray medical datasets contain irrelevant and redundant genes which cause high number of gene expression i.e. dimensionality and small sample sizes. To overcome the curse of dimensionality of the microarray datasets, modified cat swarm optimization (MCSO), a naturally inspired evolutionary algorithm, is used to select the most relevant features from the datasets. The adequacies of the classifiers are demonstrated by employing four from each binary and multi-class microarray medical datasets. Breast cancer, prostate cancer, colon tumor, leukemia datasets belong to the former and leukemia1, leukemia2, SRBCT, brain tumor1 to the latter. A number of useful performance evaluation measures including accuracy, sensitivity, specificity, confusion matrix, Gmean, F-score and the area under the receiver operating characteristic (ROC) curve are considered to examine the efficacy of the model. Other models like simple ridge regression (RR), online sequential ridge regression (OSRR), support vector machine radial basis function (SVMRBF), support vector machine polynomial (SVMPoly) and random forest are studied and analyzed for comparison. The experimental results demonstrate that KRR outperforms other models irrespective of the datasets and WKRR produces better results as compared to RKRR. Finally, when the results are compared on the basis of binary and multi-class datasets, it is found that binary class yields a little bit better result as compared to the multiclass irrespective of models.
•Two variants of Kernel ridge regression (KRR) are used for microarray medical data classification.•Modified cat swarm optimization is used for relevant feature selection.•Both binary and multiclass medical datasets are used.•The wavelet kernel ridge regression produces superior classification compared to radial basis ridge regression.
Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor ...(AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene (Agtr2) expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism. We show that selective antagonism of AT2R attenuates neuropathic but not inflammatory mechanical and cold pain hypersensitivity behaviors in mice. Agtr2-expressing macrophages (MΦs) constitute the predominant immune cells that infiltrate the site of nerve injury. Interestingly, neuropathic mechanical and cold pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs and AT2R-null hematopoietic cell transplantation. Our study identifies AT2R on peripheral MΦs as a critical trigger for pain sensitization at the site of nerve injury, and therefore proposes a translatable peripheral mechanism underlying chronic neuropathic pain.
Specialized receptors belonging to the transient receptor potential (TRP) family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive ...TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics.
Overburden and acid drainage from coal mining is transforming productive agricultural lands to unproductive wasteland in some parts of Northeast India. We have investigated the adverse effects of ...acid mine drainage on the soil of rice paddy and productivity by comparing them with non-mined land and abandoned paddy fields of Jaintia Hills in Northeast India. Pot experiments with a local rice cultivar (Myngoi) as test crop evaluated biological productivity of the contaminated soil. Contamination from overburden and acid mine drainage acidified the soil by 0.5 pH units, increased the exchangeable Al3+ content 2-fold and its saturation on clay complexes by 53%. Available sulfur and extractable heavy metals, namely Fe, Mn and Cu increased several-fold in excess of critical limits, while the availability of phosphorus, potassium and zinc contents diminished by 32–62%. The grain yield of rice was 62% less from fields contaminated with acid mine drainage than from fields that have not suffered. Similarly, the amounts of vegetation, i.e. shoots and roots, in pots filled with soil from fields that received acid mine drainage were 59–68% less than from uncontaminated land (average shoot weight: 7.9±2.12gpot−1; average root weight: 3.40±1.15gpot−1). Paddy fields recovered some of their productivity 4years after mining ceased. Step-wise multiple regression analysis affirmed that shoot weight in the pots and grain yield in field were significantly (p<0.01) and positively influenced by the soil's pH and its contents of K, N and Zn, while concentration of S in excess of threshold limits in contaminated soil significantly (p<0.01) reduced the weight of shoots in the pots and grain yield in the field.
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•Mine drainage acidified paddy soil and increased exchangeable Al3+ saturation.•Sulfur and extractable heavy metals increased in excess of critical limits.•Paddy grain yield declined by 62% in contaminated than from unaffected fields.•Concentration of excess sulfur significantly reduced biomass and grain yield.•Paddy fields recovered some of their productivity 4years after mining ceased.
The urgent need for more effective analgesic treatment options has prompted a re-evaluation of the behavioral tests used to assess pain in pre-clinical research, with an emphasis on inclusion of more ...voluntary, un-evoked behavioral assessments of pain. In order to validate voluntary gait analysis and a voluntary mechanical conflict-avoidance assay, we tested mouse models of neuropathy (spared nerve injury) and inflammation (complete Freund's adjuvant) alongside reflexive measures of mechanical and thermal hypersensitivity. To establish whether the observed changes in behavioral responses were pain-related, known analgesics (buprenorphine, gabapentin, carprofen) were also administered. Spared nerve injury persistently altered several gait indices, whereas complete Freund's adjuvant caused only transient changes. Furthermore, known analgesics could not reverse these gait changes, despite demonstrating their previously established efficacy in reflexive measures of mechanical and thermal hypersensitivity. In contrast, the mechanical conflict-avoidance assay demonstrated aversion in mice with neuropathy and inflammation-induced hypersensitivity, which could both be reversed by analgesics. We conclude that voluntary gait changes in rodent neuropathic and inflammatory pain models are not necessarily indicative of pain-related adaptations. On the other hand, mechanical conflict-avoidance represents a valid operant assay for quantifying pain-related behaviors in mice that can be reversed by known analgesics.
•A neuropathic pain model causes prolonged changes in mouse voluntary gait patterns.•An inflammatory pain model causes relatively transient gait changes.•Gait changes induced by neuropathy/inflammation are not reversible with analgesics.•A mechanical conflict-avoidance (MCA) test detects changes in these pain models.•Neuropathy/inflammation-induced changes in MCA behavior are reversed by analgesics.
Proinflammatory prostaglandin E2 is known to sensitize sensory neurons to noxious stimuli. This sensitization is mediated by the cAMP-dependent protein kinase (PKA) signal pathway. The capsaicin ...receptor TRPV1, a non-selective cation channel of sensory neurons involved in the sensation of inflammatory pain, is a target of PKA-mediated phosphorylation. Our goal was to investigate the influence of PKA on Ca2+-dependent desensitization of capsaicin-activated currents. By using site-directed mutagenesis, we created point mutations at PKA consensus sites and studied wild-type and mutant channels transiently expressed in HEK293t cells under whole-cell voltage clamp. We found that forskolin, a stimulator of adenylate cyclase, decreased desensitization of TRPV1. The selective PKA inhibitor H89 inhibited this effect. Mimicking phosphorylation at PKA consensus sites by replacing Ser-6, Ser-116, Thr-144, Thr-370, Ser-502, Ser-774, or Ser-820 with aspartate resulted in five mutations (S116D, T144D, T370D, S774D, and S820D) that exhibited decreased desensitization as well. However, disrupting phosphorylation by replacing respective sites with alanine resulted in four mutations (S6A, T144A, T370A, and S820A) with desensitization properties resembling those of the aspartate mutations. Significant changes in relative permeabilities for Ca2+ over Na+ or in capsaicin sensitivity could not explain changes in desensitization properties of mutant channels. In mutations S116A, S116D, T370A, and T370D, pretreatment of cells with forskolin did not reduce desensitization as compared with wild-type and other mutant channels. We conclude that Ser-116 and possibly Thr-370 are the most important residues involved in the mechanism of PKA-dependent reduction of desensitization of capsaicin-activated currents.
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