Pain hypersensitivity mechanisms at a glance

There are two basic categories of pain: physiological pain, which serves an important protective function, and pathological pain, which can have a major negative impact on quality of life in the context of human disease. Major progress has been made in understanding the molecular mechanisms that drive sensory transduction, amplification and conduction in peripheral pain-sensing neurons, communication of sensory inputs to spinal second-order neurons, and the eventual modulation of sensory signals by spinal and descending circuits. This poster article endeavors to provide an overview of how molecular and cellular mechanisms underlying nociception in a physiological context undergo plasticity in pathophysiological states, leading to pain hypersensitivity and chronic pain.     

Theoretical investigation of the neuronal Na+ channel SCN1A: abnormal gating and epilepsy

Epilepsy is a paroxysmal neurological disorder resulting from abnormal cellular excitability and is a common cause of disability. Recently, some forms of idiopathic epilepsy have been causally related to genetic mutations in neuronal ion channels. To understand disease mechanisms, it is crucial to understand how a gene defect can disrupt channel gating, which in turn can affect complex cellular dynamic processes. We develop a theoretical Markovian model of the neuronal Na+ channel NaV1.1 to explore and explain gating mechanisms underlying cellular excitability and physiological and pathophysiological mechanisms of abnormal neuronal excitability in the context of epilepsy. Genetic epilepsy has been shown to result from both mutations that give rise to a gain of channel function and from those that reduce the Na+ current. These data may suggest that abnormal excitation can result from both hyperexcitability and hypoexcitability, the mechanisms of which are presumably distinct, and as yet elusive. Revelation of the molecular origins will allow for translation into targeted pharmacological interventions that must be developed to treat syndromes resulting from divergent mechanisms. This work represents a first step in developing a comprehensive theoretical model to investigate the molecular mechanisms underlying runaway excitation that cause epilepsy.     

Hepatorenal syndrome

Hepatorenal syndrome (HRS) is a serious complication of liver cirrhosis with critically poor prognosis. The pathophysiological hallmark is severe renal vasoconstriction, resulting from complex changes in splanchnic and general circulations as well as systemic and renal vasoconstrictors and vasodilators. Rapid diagnosis and management are important, since recent treatment modalities including vasoconstrictor therapy can improve short-term outcome and buy time for liver transplantation, which can result in complete recovery.     

Lipid emulsions for parenteral nutrition in critical illness

Critical illness is a life-threatening multisystem process that can result in significant morbidity and mortality. In most patients, critical illness is preceded by a physiological deterioration, characterized by a catabolic state and intense metabolic changes, resulting in malnutrition and impaired immune functions. In this context, parenteral lipid emulsions may modulate inflammatory and immune reactions, depending on their fatty acid composition. These effects appear to be based on complex modifications in the composition and structure of cell membranes, through eicosanoid and cytokine synthesis and by modulation of gene expression. The pathophysiological mechanisms underlying these fatty acid-induced immune function alterations in critical ill patients are however complex and partially understood. Indeed, despite a very abundant literature, experimental and clinical data remain contradictory. The optimization of lipid emulsion composition thus represents a major challenge for clinical medicine, to adequately modulate the inflammatory pathways. In the present review, we first address the metabolic response to aggression, the effects of parenteral lipid emulsions on inflammation and immunity, and finally the controversial place of these lipid emulsions during critical illness. The analysis furthermore highlights the pathophysiological mechanisms underlying the differential effects of lipid emulsions and their potential for improving the handling of critically ill patients.     

综述与专论: 内脏痛实验动物模型的研究进展

内脏痛是内脏器官受到机械性牵拉、炎症、痉挛、应激和缺血等刺激所致的疼痛，是一种临床上常见病症。与躯体痛相比，内脏痛的产生、维持和调控机制更为复杂，因此是目前疼痛基础研究领域中的重点和难点之一。建立符合临床内脏疾病病理生理学特征的实验动物模型对研究内脏痛的产生、维持、调控机制及筛选相关内脏疾病的治疗药物具有重要意义。目前内脏痛动物模型主要按照造模刺激方式进行分类，分为炎性内脏痛模型、电刺激性内脏痛模型、机械扩张性内脏痛模型及缺血性内脏痛模型等，且每种动物模型具有不同特点。本文就近年来内脏痛基础研究中常用的实验动物模型的制备及特点做一简要综述，以期为研究者选择合适的内脏痛动物模型提供参考，为更深入研究内脏痛的复杂机制及筛选相关治疗药物奠定基础。     

Phantom limb pain: a case of maladaptive CNS plasticity?

Phantom pain refers to pain in a body part that has been amputated or deafferented. It has often been viewed as a type of mental disorder or has been assumed to stem from pathological alterations in the region of the amputation stump. In the past decade, evidence has accumulated that phantom pain might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human studies and derive suggestions for innovative interventions aimed at alleviating phantom pain.     

Regulation of cation channels in cardiac and smooth muscle cells by intracellular magnesium

Magnesium regulates various ion channels in many tissues, including those of the cardiovascular system. General mechanisms by which intracellular Mg(2+) (Mg(i)(2+)) regulates channels are presented. These involve either a direct interaction with the channel, or an indirect modification of channel function via other proteins, such as enzymes or G proteins, or via membrane surface charges and phospholipids. To provide an insight into the role of Mg(i)(2+) in the cardiovascular system, effects of Mg(i)(2+) on major channels in cardiac and smooth muscle cells and the underlying mechanisms are then reviewed. Although Mg(i)(2+) concentrations are known to be stable, conditions under which they may change exist, such as following stimulation of beta-adrenergic receptors and of insulin receptors, or during pathophysiological conditions such as ischemia, heart failure or hypertension. Modifications of cardiovascular electrical or mechanical function, possibly resulting in arrhythmias or hypertension, may result from such changes of Mg(i)(2+) and their effects on cation channels.     

Nociceptor activation and pain

This paper reviews advances in our knowledge on the physiological properties of human nociceptors and their capacity to signal pain. Conventional microneurography was used in combination with intraneural microstimulation in subjects who estimated the magnitude of pain from nociceptor stimulation. The experimental evidence favours the notion that C polymodal nociceptors can provide a peripheral neuronal basis for determination of heat pain threshold and also an essential peripheral code for suprathreshold magnitude judgments of heat pain. Furthermore, sensitized C polymodal nociceptors can contribute to hyperalgesia after a mild heat injury to hairy skin. Temporal summation is documented for dull, delayed C fibre pain, which is different in quality and less accurately projected than the fast, sharp pain from high-threshold A delta nociceptors. A segmental organization is shown for projected and referred pain from deep structures. Examples are given of central inhibition of pain by a prostaglandin synthetase inhibitor, and by physical manoeuvres such as vibration and cooling. Recent reports on microneurographic findings after nerve injury indicate that the technique may be useful for future studies on pathophysiological pain mechanisms.     

A plethora of painful molecules

Pain is a fundamental experience with a complex and multi-layered neurobiological basis. In recent years a powerful battery of techniques has been brought to bear to unravel the mechanisms by which painful stimuli are transduced and processed. There have been several recent discoveries regarding the molecular transduction mechanisms in nociceptors and novel molecular and cellular mechanisms underlying the spinal processing of painful stimuli. The mechanisms by which sensory neurons initiate hyperalgesia and touch evoked pain (allodynia) have been addressed particularly successfully in recent studies. The rich variety of key molecular players that have emerged in physiological and pathophysiological pain states reflects the sophistication and uniqueness of this vitally important sense.     

Influence of Dopaminergic Medication on Conditioned Pain Modulation in Parkinson's Disease Patients

Background

Pain is highly prevalent in patients with Parkinson’s disease (PD), but little is known about the underlying pathophysiological mechanisms. The susceptibility to pain is known to depend on ascending and descending pathways. Because parts of the descending pain inhibitory system involve dopaminergic pathways, dysregulations in dopaminergic transmission might contribute to altered pain processing in PD. Deficits in endogenous pain inhibition can be assessed using conditioned pain modulation (CPM) paradigms.

Methods

Applying such a paradigm, we investigated i) whether CPM responses differ between PD patients and healthy controls, ii) whether they are influenced by dopaminergic medication and iii) whether there are effects of disease-specific factors. 25 patients with idiopathic PD and 30 healthy age- and gender-matched controls underwent an established CPM paradigm combining heat pain test stimuli at the forearm and the cold pressor task on the contralateral foot as the conditioning stimulus. PD patients were tested under dopaminergic medication and after at least 12 hours of medication withdrawal.

Results

No significant differences between CPM responses of PD patients and healthy controls or between PD patients “on” and “off” medication were found. These findings suggest (i) that CPM is insensitive to dopaminergic modulations and (ii) that PD is not related to general deficits in descending pain inhibition beyond the known age-related decline. However, at a trend level, we found differences between PD subtypes (akinetic-rigid, tremor-dominant, mixed) with the strongest impairment of pain inhibition in the akinetic-rigid subtype.

Conclusions

There were no significant differences between CPM responses of patients compared to healthy controls or between patients “on” and “off” medication. Differences between PD subtypes at a trend level point towards different pathophysiological mechanisms underlying the three PD subtypes which warrant further investigation and potentially differential therapeutic strategies in the future.     

Induction of pain facilitation by sustained opioid exposure: relationship to opioid antinociceptive tolerance

Opioid analgesics are frequently used for the long-term management of chronic pain states, including cancer pain. The prolonged use of opioids is associated with a requirement for increasing doses to manage pain at a consistent level, reflecting the phenomenon of analgesic tolerance. It is now becoming clearer that patients receiving long-term opioid therapy can develop unexpected abnormal pain. Such paradoxical opioid-induced pain, as well as tolerance to the antinociceptive actions of opioids, has been reliably measured in animals during the period of continuous opioid delivery. Several recent studies have demonstrated that such pain may be secondary to neuroplastic changes that result, in part, from an activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM). One mechanism which may mediate such pain facilitation is through the increased activity of CCK in the RVM. Secondary consequences from descending facilitation may be produced. For example, opioid-induced upregulation of spinal dynorphin levels seem to depend on intact descending pathways from the RVM reflecting spinal neuroplasticity secondary to changes at supraspinal levels. Increased expression of spinal dynorphin reflects a trophic action of sustained opioid exposure which promotes an increased pain state. Spinal dynorphin may promote pain, in part, by enhancing the evoked release of excitatory transmitters from primary afferents. In this regard, opioids also produce trophic actions by increasing CGRP expression in the dorsal root ganglia. Increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance as manipulations which block abnormal pain also block antinociceptive tolerance. Manipulations that have blocked enhanced pain and antinociceptive tolerance include reversible and permanent ablation of descending facilitation from the RVM. Thus, opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin and enhanced release of excitatory transmitters from primary afferents. Adaptive changes produced by sustained opioid exposure including trophic effects to enhance pain transmitters suggest the need for careful evaluation of the consequences of long-term opioid administration to patients.     

Chronic hypoxia-induced alterations of key enzymes of glucose oxidative metabolism in developing mouse liver are mTOR dependent

Hypoxia is a potent regulator of gene expression and cellular energy metabolism and known to interfere with post-natal growth and development. Although hypoxia can induce adaptive changes in the developing liver, the mechanisms underlying these changes are poorly understood. To elucidate some of the adaptive changes chronic hypoxia induces in the developing liver, we studied the expression of the genes of mammalian target of rapamycin (mTOR) signaling and glucose metabolism, undertook proteomic examination with 2D gel-MS/MS of electron transport chain, and determined activities and protein expression of several key regulatory enzymes of glucose oxidative metabolism. To gain insight into the molecular mechanism underlying hypoxia-induced liver metabolic adaptation, we treated a subset of mice with rapamycin (0.5 mg/kg/day) to inhibit mTOR postnatally. Rapamycin-treated mice showed lower birth weight, lower body weight, and liver growth retardation in a pattern similar to that observed in the hypoxic mice at P30. Rapamycin treatment led to differential impact on the cytoplasmic and mitochondrial pathways of glucose metabolism. Our results suggest a decrease in mTOR activity as part of the mechanisms underlying hypoxia-induced changes in the activities of glycolytic and TCA cycle enzymes in liver. Chronic postnatal hypoxia induces mTOR-dependent differential effects on liver glycolytic and TCA cycle enzymes and as such should be studied further as they have pathophysiological implications in hepatic diseases and conditions in which hypoxia plays a role.     

Timing of propagule release significantly alters the deposition area of resulting aerial dispersal

Aim The aim of this study is to determine whether changes to the seasonal and circadian timing of propagule release can a have a significant effect on the area covered by resulting aerial dispersal. Location Western Australia. Methods Using the atmospheric pollution model (TAPM), an existing meso‐scale dispersal model, a range of release patterns was simulated and the resulting deposition compared. Comparisons were based on observations of deposition patterns and the calculated area of deposition. Results Small changes to the timing of propagule release were shown to significantly impact on the area experiencing deposition from the resulting aerial dispersal. Main conclusions Simulations performed in this study show that, for small propagules, changes to the timing of release can lead to alternate, clearly differentiable dispersal events. Small changes in both the seasonal and circadian patterns of release can have significant effects on the area that experiences deposition during the resulting dispersal event. This effect is particularly important at the landscape scale and when there is a need to quantify individual dispersal events. Predictive modelling of aerial dispersal needs to be undertaken with an understanding of the manner in which biological and environmental factors that affect the timing of propagule release can influence results. Results presented highlight the need to characterize the epidemiology of pathogenic organisms of importance to biosecurity as much as possible before they arrive.     

The scent of disease: volatile organic compounds of the human body related to disease and disorder

Hundreds of volatile organic compounds (VOCs) are emitted from the human body, and the components of VOCs usually reflect the metabolic condition of an individual. Therefore, contracting an infectious or metabolic disease often results in a change in body odour. Recent progresses in analytical techniques allow rapid analyses of VOCs derived from breath, blood, skin and urine. Disease-specific VOCs can be used as diagnostic olfactory biomarkers of infectious diseases, metabolic diseases, genetic disorders and other kinds of diseases. Elucidation of pathophysiological mechanisms underlying production of disease-specific VOCs may provide novel insights into therapeutic approaches for treatments for various diseases. This review summarizes the current knowledge on chemical and clinical aspects of body-derived VOCs, and provides a brief outlook at the future of olfactory diagnosis.     

Multiple actions of systemic artemin in experimental neuropathy

The clinical management of neuropathic pain is particularly challenging. Current therapies for neuropathic pain modulate nerve impulse propagation or synaptic transmission; these therapies are of limited benefit and have undesirable side effects. Injuries to peripheral nerves result in a host of pathophysiological changes associated with the sustained expression of abnormal pain. Here we show that systemic, intermittent administration of artemin produces dose- and time-related reversal of nerve injury-induced pain behavior, together with partial to complete normalization of multiple morphological and neurochemical features of the injury state. These effects of artemin were sustained for at least 28 days. Higher doses of artemin than those completely reversing experimental neuropathic pain did not elicit sensory or motor abnormalities. Our results indicate that the behavioral symptoms of neuropathic pain states can be treated successfully, and that partial to complete reversal of associated morphological and neurochemical changes is achievable with artemin.     

Ontogeny of the pain

The article gives an overview of developmental aspects of the ontogeny of pain both in experimental models and in children. The whole article is devoted to the ontogenesis in pain perception and the possible influence on it. The role of endogenous opioids on the development of pain and other important substances such as serotonin, nerve growth factor (NGF) and nicotine are mentioned. There are also important differences of the ontogenesis of thermal and mechanical nociceptive stimulation. The physiological and pathophysiological findings are the backgrounds for principles of treatment, taking into account the special status of analgesics during ontogeny. In particular there are mentioned the special effects of endogenous opioids and especially morphine. It describes the role of vitamin D and erythropoietin during the development of pain perception. This article also mentioned the critical developmental periods in relation to the perception of pain. The attention is paid to stress and immunological changes during the ontogeny of pain. Another important role is played by microglia. The work is concluded by some statements about the use of physiological and pathophysiological findings during the treatment of pain in pediatric practice. Codein analgesia is also described because codein starts to be very modern drug with the dependence.     

BEVSIM: Battery electric vehicle sustainability impact assessment model

To achieve climate neutrality ambitions, greenhouse gas emissions from the transport sector need to be reduced by at least 90% by 2050. To support industry and policy makers on mitigating actions on climate goals it is important to holistically compare and reduce life cycle environmental impacts of road passenger vehicles. A web-based sustainability assessment tool named battery electric vehicle sustainability impact assessment model, BEVSIM, is developed to assess the environmental, circularity, and economic performance of the materials, sub-systems, parts, and individual components of battery electric vehicles and internal combustion engine vehicles. This tool allows to measure and compare impacts resulting from recycling technologies, end-of-life scenarios, and future scenarios resulting from changes in grid mixes. This paper explains the purpose of the tool, its functionality and design as well as the underlying assumptions.     

Cell volume regulation in the nervous system

There is good evidence that the three main compartments of the brain, i.e. extracellular space, neurones and glial cells, change their volume during physiological and pathophysiological neuronal activity. However, there is strikingly little knowledge about the mechanisms underlying such alterations in cell volume. For this purpose, a better understanding of the electrophysiological behavior of the neurones and glial cells during volume changes is necessary. Examples are discussed for which changes in cell volume can be derived from the underlying changes in membrane permeabilities. Volume regulatory mechanisms in the brain have not been described under isotonic conditions. However, a rapid volume regulatory decrease is occurring in cultured glial cells during exposure to hypotonic solutions. In contrast, in these cells no volume regulatory increase was found during superfusion with hypertonic media. On the other hand, the entire brain is able to compensate chronic hypertonic perturbations within hours to days. Interestingly, not only ion fluxes induce cellular volume changes but, in turn, water movements can also influence ion fluxes in both neurones and glial cells. With respect to this it should be considered that volume regulatory membrane processes might not exclusively be activated by changes in transmembranal ion gradient, but also by changes of membrane surface shape. Future studies on cellular mechanisms of volume regulation in the brain should imply a combined use of recent techniques such as computerized video-imaging, radiotracer flux measurements and ion-sensitive microelectrodes in defined cell cultures. Optical monitoring and ion-sensitive microelectrodes should enable measurements of volume changes in identified cellular elements of intact nervous structures such as brain slices.     

The method of the integral evaluation of the behavioral depression in rats

A new method of the evaluation of behavioral depression was developed based on a ranged scale of changes in a number of depressive symptoms in behavior and general state of animals. The method makes it possible to evaluate the individual expression of depressive symptoms in rats and can be used for revealing a correlation between the decrease in motivation level in depressive animals and alterations of some pathophysiological parameters.     

An ontogenetic perspective on individual differences

Phenotypic differences among individuals can arise during any stage of life. Although several distinct processes underlying individual differences have been defined and studied (e.g. parental effects, senescence), we lack an explicit, unified perspective for understanding how these processes contribute separately and synergistically to observed variation in functional traits. We propose a conceptual framework based on a developmental view of life-history variation, linking each ontogenetic stage with the types of individual differences originating during that period. In our view, the salient differences among these types are encapsulated by three key criteria: timing of onset, when fitness consequences are realized, and potential for reversibility. To fill a critical gap in this framework, we formulate a new term to refer to individual differences generated during adulthood—reversible state effects. We define these as ‘reversible changes in a functional trait resulting from life-history trade-offs during adulthood that affect fitness’, highlighting how the adult phenotype can be repeatedly altered in response to environmental variation. Defining individual differences in terms of trade-offs allows explicit predictions regarding when and where fitness consequences should be expected. Moreover, viewing individual differences in a developmental context highlights how different processes can work in concert to shape phenotype and fitness, and lays a foundation for research linking individual differences to ecological and evolutionary theory.