Calcium release-activated calcium channels and pain

Calcium release-activated calcium (CRAC) channels are unique among ion channels that are activated in response to depletion of intracellular calcium stores and are highly permeable to Ca²⁺ compared to other cations. CRAC channels mediate an important calcium signal for a wide variety of cell types and are well studied in the immune system. They have been implicated in a number of disorders such as immunodeficiency, musculosketal disorders and cancer. There is growing evidence showing that CRAC channels are expressed in the nervous system and are involved in pathological conditions including pain. This review summarizes the expression, distribution, and function of the CRAC channel family in the dorsal root ganglion, spinal cord and some brain regions, and discusses their functional significance in neurons and glial cells and involvement in nociception and chronic pain. Although further studies are needed to understand how these channels are activated under physiological conditions, the recent findings indicate that the CRAC channel Orai1 is an important player in pain modulation and could represent a new target for pathological pain.     

慢性疼痛与皮层-边缘系统

慢性疼痛作为最常见的临床症状之一，已被认为是全球性的公共健康问题. 然而，目前急性疼痛转化为慢性疼痛（即疼痛慢性化）的机制尚不清楚，如何防治急性疼痛转化为慢性疼痛仍然是临床亟待解决的问题. 影像学研究表明，编码疼痛情绪、动机和记忆的脑区涉及皮层-边缘系统，而编码持续性疼痛的脑区也主要涉及该系统. 基于此，本文概述了慢性疼痛患者在情绪、动机和记忆等方面的行为异常，并详细讨论了慢性疼痛患者皮层-边缘系统的结构和功能变化. 其次，本文以慢性腰背痛为例，总结了可能预测疼痛慢性化的影像学指标，如内侧前额叶皮层与伏隔核以及海马的功能连接、背内侧前额叶皮层-杏仁核-伏隔核之间的功能连接均可预测1年后腰背痛疼痛慢性化的发展. 此外，基于现有的疼痛慢性化理论模型，本文指出疼痛慢性化可能涉及患者对负面情绪的强化学习以及奖赏和应激系统的功能失调. 最后，根据目前研究仍存在的问题和局限，本文对未来的研究方向和方法提出了建议.     

A Quantitative Electroencephalographic Correlate of Sustained Attention Processing

The objective of the present investigation was to develop a quantitative electroencephalographic measure (qEEG) that is sensitive and specific to changes in sustained human performance. A principal components analysis (PCA) was performed on the qEEG obtained from participants during a continuous performance test. Measures of sensitivity (proportion of correctly identified correct responses, or hits) and specificity (proportion of correctly identified incorrect responses, or misses) were calculated to assess the classification accuracy of each newly derived component. PCA solutions produced a right hemisphere component comprised of beta-wave activity measured from four unipolar sites (F8, C6a, C6, and T4) that appeared to be sensitive and specific to changes in human performance. Results provide evidence for the validity of a right hemisphere qEEG measure that is sensitive and specific to changes in sustained human performance. Consistent with the findings of previous research, the present findings implicate the right cerebral hemisphere in the sustained attention process.     

Role of Astrocytes in Pain

Over the last decade, a series of studies has demonstrated that glia in the central nervous system play roles in many aspects of neuronal functioning including pain processing. Peripheral tissue damage or inflammation initiates signals that alter the function of the glial cells (microglia and astrocytes in particular), which in turn release factors that regulate nociceptive neuronal excitability. Like immune cells, these glial cells not only react at sites of central and/or peripheral nervous system damage but also exert their action at remote sites from the focus of injury or disease. As well as extensive evidence of microglial involvement in various pain states, there is also documentation that astrocytes are involved, sometimes seemingly playing a more dominant role than microglia. The interactions between astrocytes, microglia and neurons are now recognized as fundamental mechanisms underlying acute and chronic pain states. This review focuses on recent advances in understanding of the role of astrocytes in pain states.     

Emotional regulation of pain: the role of noradrenaline in the amygdala

The perception of pain involves the activation of the spinal pathway as well as the supra-spinal pathway,which targets brain regions involved in affective and cognitive processes.Pain and emotions have the capacity to influence each other reciprocally;negative emotions,such as depression and anxiety,increase the risk for chronic pain,which may lead to anxiety and depression.The amygdala is a key-player in the expression of emotions,receives direct nociceptive information from the parabrachial nucleus,and is densely innervated by noradrenergic brain centers.In recent years,the amygdala has attracted increasing interest for its role in pain perception and modulation.In this review,we will give a short overview of structures involved in the pain pathway,zoom in to afferent and efferent connections to and from the amygdala,with emphasis on the direct parabrachio-amygdaloid pathway and discuss the evidence for amygdala’s role in pain processing and modulation.In addition to the involvement of the amygdala in negative emotions during the perception of pain,this brain structure is also a target site for many neuromodulators to regulate the perception of pain.We will end this article with a short review on the effects of noradrenaline and its role in hypoalgesia and analgesia.     

Pain perception in relation to emotional learning

Noninvasive brain imaging has established the participation of the cortex in pain perception and identified a long list of brain structures involved. More recent studies show the interaction between clinical chronic pain conditions and the reorganization of the brain functionally, anatomically, and chemically. Mechanisms underlying this reorganization hint to essential links between pain, especially its affective component with emotional learning and memory. This review is a discussion of the rationale and evidence for the interaction between these modalities, emphasizing underlying mechanisms.     

Regulation of T-type calcium channels in the peripheral pain pathway

Recent evidence strongly suggests that both central and peripheral T-type Ca(2+) channels enhance somatic and visceral nociceptive inputs, as well as that regulation of T-type Ca(2+) channel function can result in significant changes of pain threshold in a variety of animal models. Therefore, T-type Ca(2+) channels in peripheral and central pain pathways, although previously unrecognized, may have great importance as targets for developing new therapies against pain. This is particularly critical in cases in which currently available treatments are limited due to serious side effects or are not consistently effective (e.g., chronic neuropathic pain). In this review, we summarize recent studies of the regulation of T-type channels in peripheral sensory neurons by means of redox agents and neuroactive steroids, as well as studies of the function of these channels in the pathophysiology of neuropathic pain.     

The IL-23/IL-17 pathway in human chronic inflammatory diseases – new insight from genetics and targeted therapies

Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthritis and psoriasis cause significant morbidity and are a considerable burden for the patients in terms of pain, impaired function and diminished quality of life, as well as for society, because of the associated high health-care costs, and loss of productivity. Our limited understanding of the pathogenic mechanisms involved in these diseases currently hinders early diagnosis and the development of more specific and effective therapies.The past years have been marked by considerable progress in our insight of the genetic basis of many diseases. In particular, genome-wide association studies (GWAS) performed with thousands of patients have provided detailed information about the genetic variants associated with a large number of chronic inflammatory diseases. These studies have brought to the forefront many genes linked to signaling pathways that were not previously known to be involved in pathogenesis, pointing to new directions in the study of disease mechanisms. GWAS also provided fundamental evidence for a key role of the immune system in the pathogenesis of these diseases, because many of the identified loci map to genes involved in different immune processes. However, the mechanisms by which disease-associated genetic variants act on disease development and the targeted cell populations remain poorly understood. The challenge of the post-GWAS era is to understand how these variants affect pathogenesis, to allow translation of genetic data into better diagnostics and innovative treatment strategies.Here, we review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients.     

Ionotropic Glutamate Receptors in Spinal Nociceptive Processing

Glutamate is the predominant excitatory transmitter used by primary afferent synapses and intrinsic neurons in the spinal cord dorsal horn. Accordingly, ionotropic glutamate receptors mediate basal spinal transmission of sensory, including nociceptive, information that is relayed to supraspinal centers. However, it has become gradually more evident that these receptors are also crucially involved in short- and long-term plasticity of spinal nociceptive transmission, and that such plasticity have an important role in the pain hypersensitivity that may result from tissue or nerve injury. This review will cover recent findings on pre- and postsynaptic regulation of synaptic function by ionotropic glutamate receptors in the dorsal horn and how such mechanisms contribute to acute and chronic pain.     

Evidence-based hydro- and balneotherapy in Hungary—a systematic review and meta-analysis

Balneotherapy is appreciated as a traditional treatment modality in medicine. Hungary is rich in thermal mineral waters. Balneotherapy has been in extensive use for centuries and its effects have been studied in detail. Here, we present a systematic review and meta-analysis of clinical trials conducted with Hungarian thermal mineral waters, the findings of which have been published by Hungarian authors in English. The 122 studies identified in different databases include 18 clinical trials. Five of these evaluated the effect of hydro- and balneotherapy on chronic low back pain, four on osteoarthritis of the knee, and two on osteoarthritis of the hand. One of the remaining seven trials evaluated balneotherapy in chronic inflammatory pelvic diseases, while six studies explored its effect on various laboratory parameters. Out of the 18 studies, 9 met the predefined criteria for meta-analysis. The results confirmed the beneficial effect of balneotherapy on pain with weight bearing and at rest in patients with degenerative joint and spinal diseases. A similar effect has been found in chronic pelvic inflammatory disease. The review also revealed that balneotherapy has some beneficial effects on antioxidant status, and on metabolic and inflammatory parameters. Based on the results, we conclude that balneotherapy with Hungarian thermal-mineral waters is an effective remedy for lower back pain, as well as for knee and hand osteoarthritis.     

Utilizing the Quantitative Electroencephalograph (qEEG) to Objectively Document the Nature and Severity of Concussions in Junior Hockey Players: A Pilot Investigation

Concussions represent a major concern for hockey teams. During one winter season, all players on two Junior Hockey Teams were assessed in order to establish an incidence baseline for concussions. The qEEG was utilized as it measures the probability of concussion and its severity. The SCL 90-R and CNS questionnaire were used to provide insight into various aspects of cognitive functioning. Results indicated that of the players assessed (N?=?46) approximately two-thirds (N?=?32) tested positive for concussions. A minority of the concussions were assessed as mild (N?=?13), while 19 were assessed as moderately severe. The most common sites indicated as injured were F8 and T6 (right side of head) and O1 and O2 (back of head) and F7 (left front of head). A comparison of the questionnaire results to expected behavioural issues are discussed. This appears to be one of the first studies of junior hockey players using an objective measure of study (qEEG).     

Big roles for small GTPases in the control of directed cell movement

Small GTPases are involved in the control of diverse cellular behaviours, including cellular growth, differentiation and motility. In addition, recent studies have revealed new roles for small GTPases in the regulation of eukaryotic chemotaxis. Efficient chemotaxis results from co-ordinated chemoattractant gradient sensing, cell polarization and cellular motility, and accumulating data suggest that small GTPase signalling plays a central role in each of these processes as well as in signal relay. The present review summarizes these recent findings, which shed light on the molecular mechanisms by which small GTPases control directed cell migration.     

Democratic organization of the thalamocortical neural ensembles in nociceptive signal processing

Acute pain is a warning protective sensation for any impending harm. However, chronic pain syndromes are often resistant diseases that may consume large amount of health care costs. It has been suggested by recent studies that pain perception may be formed in central neural networks via large-scale coding processes, which involves sensory, affective, and cognitive dimensions. Many central areas are involved in these processes, including structures from the spinal cord, the brain stem, the limbic system, to the cortices. Thus, chronic painful diseases may be the result of some abnormal coding within this network. A thorough investigation of coding mechanism of pain within the central neuromatrix will bring us great insight into the mechanisms responsible for the development of chronic pain, hence leading to novel therapeutic interventions for pain management.     

Toxoplasma: the next 100years

It has been 100 years since Toxoplasma gondii was initially described in Tunis by Nicolle and Manceaux (1908) in the tissues of the gundi (Ctenodoactylus gundi) and in Brazil by Splendore (1908) in the tissues of a rabbit. T. gondii is a ubiquitous, Apicomplexan parasite of warm-blooded animals that can cause several clinical syndromes including encephalitis, chorioretinitis and congenital infection. Due to the extensive repertoire of applicable experimental techniques available for this pathogen it has become a model organism for the study of intracellular pathogens. Data obtained from genome-wide expression studies, including ChIP on chip and proteomics surveys, are refining our understanding of the genetic networks involved in the developmental biology of this pathogen as well as the interactions of the parasite with its host. This review addresses recent advances in our understanding of the developmental biology and host-pathogen relationships of T. gondii.     

Pain genetics: past, present and future

Chronic pain is a classic example of gene × environment interaction: inflammatory and/or nerve injuries are known or suspected to be the etiology of most chronic pain syndromes, but only a small minority of those subjected to such injuries actually develop chronic pain. Once chronic pain has developed, pain severity and analgesic response are also highly variable among individuals. Although animal genetics studies have been ongoing for over two decades, only recently have comprehensive human twin studies and large-scale association studies been performed. Here, I review recent and accelerating progress in, and continuing challenges to, the identification of genes contributing to such variability. Success in this endeavor will hopefully lead to both better management of pain using currently available therapies and the development and/or prioritizing of new ones.     

Mechanisms of central sensitization, neuroimmunology & injury biomechanics in persistent pain: implications for musculoskeletal disorders.

This review will offer an overview of the mechanistic pathways of chronic pain associated with musculoskeletal disorders (MSDs). Traditional electrophysiological pain pathways of these injuries will be reviewed. In addition, recent research efforts in persistent pain have characterized a cascade of neuroimmunologic events in the central nervous system that manifests in pain behaviors and neurochemical nociceptive responses. Physiologic changes in the central nervous system will be covered as they pertain to the interplay of these two areas, and also as they focus on MSDs and injuries. One such injury leading to persistent pain is radiculopathy, which results from nerve root compression or impingement and leads to low back pain. This painful syndrome will be used as an example to provide a context for presenting immune mechanisms of chronic pain and their relationship to injury. Measures of injury biomechanics are presented in the context of the resulting pain responses, including behavioral sensitivity, local structural changes, and cellular and molecular changes in the CNS. Lastly, based on these findings and others, a discussion is provided highlighting areas of future work to help elucidate methods of injury diagnosis and development of therapeutic treatments.     

Metformin relieves neuropathic pain after spinal nerve ligation via autophagy flux stimulation

Neuropathic pain is a well‐known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many diseases, including neuropathic pain. Emerging evidence suggests that metformin relieves neuropathic pain in several neuropathic pain models; however, metformin's cellular and molecular mechanism for pain relief remains unknown. In this study, we investigated the therapeutic effects of metformin on pain relief after spinal nerve ligation (SNL) and its underlying mechanism of autophagy regulation. Behavioural analysis, histological assessment, expression of c‐Fos and molecular biological changes, as well as ultrastructural features, were investigated. Our findings showed that the number of autophagosomes and expression of autophagy markers, such as LC3 and beclin1, were increased, while the autophagy substrate protein p62, as well as the ubiquitinated proteins, were accumulated in the ipsilateral spinal cord. However, metformin enhanced the expression of autophagy markers, while it abrogated the abundance of p62 and ubiquitinated proteins. Blockage of autophagy flux by chloroquine partially abolished the apoptosis inhibition and analgesic effects of metformin on SNL. Taken together, these results illustrated that metformin relieved neuropathic pain through autophagy flux stimulation and provided a new direction for metformin drug development to treat neuropathic pain.     

视网膜S-电位和水平细胞

S-电位的发现揭开了视网膜神经元细胞内研究的序幕。细胞内染色技术已证明 S-电位起源于水平细胞。本文评述这一领域的主要进展,特别是结合外网状层神经元回路的研究,讨论对各种水平细胞的感受细胞输入及其相互作用。也将论及水平细胞在视信息处理过程中的作用。     

Is vibration truly an injurious stimulus in the human spine?

Epidemiological data at one time was taken to suggest that chronic vibrations—for example operating vehicles with low-quality seats—contributed to intervertebral disc degeneration and lower back pain. More recent discussions, based in part upon extended twin studies, have cast doubt upon this interpretation, and question how much of the vibration is actually transmitted to the spine during loading. This review summarizes our recent survey of the current state of knowledge. In particular, we note that current studies are lacking a detailed factorial exploration of frequency, amplitude, and duration; this may be the primary cause for inconclusive and/or contradictory studies. It is our conclusion that vibrations are still an important consideration in discogenic back pain, and further controlled studies are warranted to definitively examine the underlying hypothesis: that chronic vibration can influence IVD cell biology and tissue mechanics.     

Association Between Antioxidant Intake/Status and Obesity: a Systematic Review of Observational Studies

The global prevalence of obesity has doubled in recent decades. Compelling evidences indicated that obesity was associated with lower concentrations of specific antioxidants which may play a role in the development of obesity-related diseases such as cardiovascular disease. The present review aimed to synthesize the evidence from studies on the association between obesity and antioxidant micronutrients in a systematic manner. Data bases including MEDLINE, Science Direct, and Cochrane were searched from inception to October 2015. Thirty-one articles were reviewed using the MOOSE checklist. Lower concentrations of antioxidants have been reported in obese individuals among age groups worldwide. Circulatory levels of carotenoids, vitamins E and C, as well as zinc, magnesium, and selenium were inversely correlated with obesity and body fat mass. However, studies demonstrated inconsistencies in findings. Lower status of carotenoids, vitamins E and C, zinc, magnesium, and selenium appears to be associated with adiposity. Intervention studies may be needed to establish the causality of these associations.