Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome

Fibromyalgia (FM) pain is frequent in the general population but its pathogenesis is only poorly understood. Many recent studies have emphasized the role of central nervous system pain processing abnormalities in FM, including central sensitization and inadequate pain inhibition. However, increasing evidence points towards peripheral tissues as relevant contributors of painful impulse input that might either initiate or maintain central sensitization, or both. It is well known that persistent or intense nociception can lead to neuroplastic changes in the spinal cord and brain, resulting in central sensitization and pain. This mechanism represents a hallmark of FM and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established only minimal nociceptive input is required for the maintenance of the chronic pain state. Additional factors, including pain related negative affect and poor sleep have been shown to significantly contribute to clinical FM pain. Better understanding of these mechanisms and their relationship to central sensitization and clinical pain will provide new approaches for the prevention and treatment of FM and other chronic pain syndromes.     

糖皮质激素在慢性疼痛中的双重作用机制

糖皮质激素(glucocorticoid,GC)是下丘脑-垂体-肾上腺(hypothalamic-pituitary-adrenal,HPA)轴分泌的最终效应激素,通过与糖皮质激素受体(glucocorticoid receptors,GR)结合行使功能。研究发现,GC在慢性疼痛中表现双重作用,内源性GC作为抗炎类固醇通过募集免疫细胞、抑制激酶通路、调节神经胶质细胞在部分类型的神经病理性疼痛及炎性痛中发挥抑痛作用,但在应激情况下,GC水平异常升高参与中枢神经系统神经元的凋亡、兴奋、记忆等,通过调控不同的信号反应或微环境促进病理性疼痛。本文综述GC在慢性疼痛中的作用,了解其发挥镇痛或致痛的双重作用机制。     

Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia

Stress is a state of disharmony, or threatened homeostasis. A stressor could have a psychological origin or a biological origin. Societies have become more intricate with industrialization, and modern individuals try to adapt to the new defiance by forcing their stress response system. The main component of the stress response network is the autonomic nervous system. The present article reviews current knowledge on autonomic dysfunction in fibromyalgia. Sympathetic hyperactivity has been consistently described by diverse groups of investigators. Fibromyalgia is proposed to be a sympathetically maintained neuropathic pain syndrome, and genomic data support this contention. Autonomic dysfunction may also explain other fibromyalgia features not related to pain.     

Basic mechanisms of pain associated with deep tissues.

There are important differences in pain arising from deep tissues in comparison to cutaneous pain. These differences can be partially explained by the unique organization of nociceptive systems activated by stimulation of muscle, joint, or viscera. Recent evidence also indicates that stimulation of deep tissues can produce long-lasting changes in central nervous system excitability and, therefore, may play a prominent role in persistent or chronic pain conditions. These findings have important implications for the treatment of chronic deep tissue pain conditions.     

Electrical stimulation of peripheral and central pathways for the relief of musculoskeletal pain

One method for the treatment of chronic musculoskeletal pain involves stimulation of the peripheral or central nervous system. Such stimulation includes transcutaneous electrical nerve stimulation, dorsal column stimulation, and deep brain stimulation. This review discusses the clinical use of electrical stimulation for the relief of musculoskeletal pain, and describes the results of studies conducted in our laboratory suggesting that such stimulation reduces pain transmission along sensory-discriminative pathways.     

Le syndrome douloureux chronique pelvien chez l’homme. Quelle physiopathologie? Quel traitement?

Chronic pelvic pain, in young men or elderly men, has always been a challenge to the medical profession, raising problems of assessment and management. Chronic pelvic pain has a high prevalence, which is underestimated as indicated by the following figures: 4% to 8% of patients consulting chronic pain centres, 15% of patients consulting a urologist for symptoms of chronic prostatitis with alteration of quality of life, 70,000 cases of chronic cystitis per year in the USA. The circumstances of onset are multiple: postoperative, after minor or major trauma or postinfectious, sometimes without any particular aetiology and often in a multifactorial context. The pathophysiology is therefore vague and poorly elucidated, as only about 5% of cases of chronic prostatitis have a bacterial cause. However, any form of stimulation activates pain pathways with neurogenic inflammation followed by central sensitization and modification of neuronal plasticity, and finally chronic refractory pain with organic dysfunction. This mechanism is currently proposed in numerous publications concerning postoperative chronic pelvic pain and refractory cystitis and chronic prostatitis. The pathophysiology of these types of pain is probably therefore neurogenic. In the absence of stimulation, a pudendal nerve tunnel syndrome can be suggested. The treatment of chronic pelvic pain in men can be considered in the following way: aetiological treatment whenever possible, neurogenic medical treatment (tricyclic antidepressants for continuous pain, anticonvulsants for intermittent pain, NMDA receptor antagonists in the case of failure), treatment of organic dysfunction, pudendal nerve analgesic block in the case of suspected tunnel syndrome and global treatment of patient with impaired quality of life. In conclusion, a better pathophysiological approach to these forms of chronic pelvic pain can improve these difficult patients.     

Presynaptic and Postsynaptic Cortical Mechanisms of Chronic Pain

Long-term potentiation (LTP) is a cellular model for learning and memory and believed to be critical for plastic changes in the brain. Depending on the central nervous system region, LTP has been proposed to contribute to many key physiological functions and pathological conditions, such as learning/memory, chronic pain, and drug addiction. While the induction of LTP in general requires activation of postsynaptic glutamate receptors, the expression of LTP can be mediated by postsynaptic mechanisms and/or presynaptic enhancement of glutamate release. In this review, we will evaluate recent progress made in the mechanisms of LTP in the anterior cingulate cortex (ACC) and explore its functional significance in synaptic changes after peripheral injury. Recent findings suggest that while ACC LTP in brain slice preparations is postsynaptically induced and expressed, injury triggered synaptic potentiation in the ACC contains both presynaptic enhancement of glutamate release and postsynaptic potentiation of AMPA receptor-mediated responses. Understanding presynaptic and postsynaptic mechanisms for ACC potentiation may help us to treat chronic pain in near future.     

Dysregulated Src upregulation of NMDA receptor activity: a common link in chronic pain and schizophrenia

Upregulation of N-methyl-D-aspartate (NMDA) receptor function by the nonreceptor protein tyrosine kinase Src has been implicated in physiological plasticity at glutamatergic synapses. Here, we highlight recent findings suggesting that aberrant Src upregulation of NMDA receptors may also be key in pathophysiological conditions. Within the nociceptive processing network in the dorsal horn of the spinal cord, pathologically increased Src upregulation of NMDA receptors is critical for pain hypersensitivity in models of chronic inflammatory and neuropathic pain. On the other hand, in the hippocampus and prefrontal cortex, the physiological upregulation of NMDA receptors by Src is blocked by neuregulin 1-ErbB4 signaling, a pathway that is genetically implicated in the positive symptoms of schizophrenia. Thus, either over-upregulation or under-upregulation of NMDA receptors by Src may lead to pathological conditions in the central nervous system. Therefore, normalizing Src upregulation of NMDA receptors may be a novel therapeutic approach for central nervous system disorders, without the deleterious consequences of directly blocking NMDA receptors.     

Chronic stimulation of the septal area for the relief of intractable pain

Although brain stimulation techniques have changed the treatment of pain, their rationale has not yet been fully proved, and their clinical results are still frequently erratic or contradictory. In an attempt to provide alternate sites for stimulation, 10 patients were, in addition to conventional targets, chronically implanted at the septal area. Satisfactory relief of dysesthetic pain was induced by septal stimulation in 60% of the cases overall, without untoward effects. The follow-up ranged from 1 to 42 months. The available data conceivably suggest other mechanisms than the presumed exclusive activation of opiomimetic structures. They also seem to indicate that the septal area may be a suitable target for chronic stimulation.     

Stress of different types increases the proinflammatory load in rheumatoid arthritis

Stress in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) stimulates proinflammatory mechanisms due to the defect of stress response systems (for example, the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis). Among other mechanisms, the loss of sympathetic nerve fibers in inflamed tissue and inadequate cortisol secretion in relation to inflammation lead to an enhanced proinflammatory load in RA. Stress and the subsequent stimulation of inflammation (systemic and local) lead to increased sensitization of pain and further defects of stress response systems (vicious cycle of stress, pain, and inflammation).     

Visceral nociception: peripheral and central aspects of visceral nociceptive systems

Discomfort and pain are the sensations most commonly evoked from viscera. Most nociceptive signals that originate from visceral organs reach the central nervous system (c.n.s.) via afferent fibres in sympathetic nerves, whereas parasympathetic nerves contain mainly those visceral afferent fibres concerned with the non-sensory aspects of visceral afferent function. Noxious stimulation of viscera activates a variety of specific and non-specific receptors, the vast majority of which are connected to unmyelinated afferent fibres. Studies on the mechanisms of visceral sensation can thus provide information on the more general functions of unmyelinated afferent fibres. Specific visceral nociceptors have been found in the heart, lungs, testes and biliary system, whereas noxious stimulation of the gastro-intestinal tract appears to be detected mainly by non-specific visceral receptors that use an intensity-encoding mechanism. Visceral nociceptive messages are conveyed to the spinal cord by relatively few visceral afferent fibres which activate many central neurons by extensive functional divergence through polysynaptic pathways. Impulses in visceral afferent fibres excite spinal cord neurons also driven by somatic inputs from the corresponding dermatome (viscero-somatic neurons). Noxious intensities of visceral stimulation are needed to activate viscero-somatic neurons, most of which can also be excited by noxious stimulation of their somatic receptive fields. The visceral input to some viscero-somatic neurons in the spinal cord can be mediated via long supraspinal loops. Pathways of projection of viscero-somatic neurons include the spino-reticular and spino-thalamic tracts. All these findings give experimental support to the 'convergence-projection' theory of referred visceral pain. Visceral pain is the consequence of the diffuse activation of somato-sensory nociceptive systems in a manner that prevents accurate spatial discrimination or localization of the stimuli. Noxious stimulation of visceral receptors triggers general reactions of alertness and arousal and evokes unpleasant and poorly localized sensory experiences. This type of response may be a feature of sensory systems dominated by unmyelinated afferent inputs.     

Magnetic resonance imaging for chronic pain: diagnosis,manipulation, and biomarkers

Pain is a multidimensional subjective experience with biological, psychological, and social factors. Whereas acute pain can be a warning signal for the body to avoid excessive injury, long-term and ongoing pain may be developed as chronic pain. There are more than 100 million people in China living with chronic pain, which has raised a huge socioeconomic burden. Studying the mechanisms of pain and developing effective analgesia approaches are important for basic and clinical research. Recently, with the development of brain imaging and data analytical approaches, the neural mechanisms of chronic pain have been widely studied. In the first part of this review, we briefly introduced the magnetic resonance imaging and conventional analytical approaches for brain imaging data. Then, we reviewed brain alterations caused by several chronic pain disorders, including localized and widespread primary pain, primary headaches and orofacial pain, musculoskeletal pain, and neuropathic pain, and present meta-analytical results to show brain regions associated with the pathophysiology of chronic pain. Next, we reviewed brain changes induced by pain interventions, such as pharmacotherapy, neuromodulation, and acupuncture. Lastly, we reviewed emerging studies that combined advanced machine learning and neuroimaging techniques to identify diagnostic, prognostic, and predictive biomarkers in chronic pain patients.     

Molecular and cellular mechanisms of excitotoxic neuronal death

Glutamate receptor-mediated excitatory neurotransmission plays a key role in neural development, differentiation and synaptic plasticity. However, excessive stimulation of glutamate receptors induces neurotoxicity, a process that has been defined as excitotoxicity. Excitotoxicity is considered to be a major mechanism of cell death in a number of central nervous system diseases including stroke, brain trauma, epilepsy and chronic neurodegenerative disorders. Unfortunately clinical trials with glutamate receptor antagonists, that would logically prevent the effects of excessive receptor activation, have been associated with untoward side effects or little clinical benefit. Therefore, uncovering molecular pathways involved in excitotoxic neuronal death is of critical importance to future development of clinical treatment of many neurodegenerative disorders where excitotoxicity has been implicated. This review discusses the current understanding of the molecular and cellular mechanisms of excitotoxicity and their roles in the pathogenesis of diseases of the central nervous system.     

Pain genes

Pain, which afflicts up to 20% of the population at any time, provides both a massive therapeutic challenge and a route to understanding mechanisms in the nervous system. Specialised sensory neurons (nociceptors) signal the existence of tissue damage to the central nervous system (CNS), where pain is represented in a complex matrix involving many CNS structures. Genetic approaches to investigating pain pathways using model organisms have identified the molecular nature of the transducers, regulatory mechanisms involved in changing neuronal activity, as well as the critical role of immune system cells in driving pain pathways. In man, mapping of human pain mutants as well as twin studies and association studies of altered pain behaviour have identified important regulators of the pain system. In turn, new drug targets for chronic pain treatment have been validated in transgenic mouse studies. Thus, genetic studies of pain pathways have complemented the traditional neuroscience approaches of electrophysiology and pharmacology to give us fresh insights into the molecular basis of pain perception.     

Structural,biological, and pharmacological strategies for the inhibition of nerve growth factor

Nerve growth factor (NGF) is critical for the development and maintenance of sympathetic and sensory neurons in the developing nervous system, including nociceptors. In the adult nervous system, NGF is known to produce significant pain signals by binding to the TrkA and p75NTR receptors. Several pathological pain disorders are associated with nerve growth factor dysregulation, including neuropathic pain, osteoarthritic pain, and hyperalgesia. Currently, clinical management of these pathologies has relied on the use of opioid and non-steroidal anti-inflammatory drugs (NSAID). However, several chronic pain conditions demonstrate insensitivity to NSAID treatment or the development of detrimental opioid-related side effects, including addiction. As NGF plays an important role in pain generation; antibodies, small molecules and peptides have been designed to antagonize NGF. In this review, we discuss the structural biology of NGF ligand/receptor interaction, and we review current biological and pharmacological strategies to modulate NGF-related pathologies.     

深部脑刺激作用机制的探讨

深部脑刺激器（deep brain stimulator）,也经常被称为脑起搏器,是可植入人体设备,并连续不断地传送刺激脉冲到深部脑组织的特定区域,即所谓的深部脑刺激（deep brain stimulation,DBS）.迄今为止,深部脑刺激是治疗严重顽固抗药性运动障碍疾病（如帕金森病,原发性震颤及肌张力异常等）的最有效的外科治疗手段之一.此外,广大的科研工作者也不断地探索应用DBS治疗其他神经及精神异常（如,癫痫和强迫症）的新的临床应用.尽管应用DBS治疗运动障碍非常有效,并也迅速被探索性地应用到其他神经障碍治疗中,但其作用机制仍然不是十分清楚,成为学者们争论的热点.DBS治疗效果的作用机制通常有两种基本的观点：高频刺激抑制学说及高频刺激兴奋学说.基于最近发表的关于中枢神经系统内的高频刺激效应的资料、数据及相关评论,两种机制共存并发挥作用的DBS作用假说被提出,认为DBS通过施加高频刺激干扰并控制了核团病理性紊乱随机活动,同时施加兴奋性刺激到其他基底节的网络,以实现对帕金森病的治疗.     

Structural,biological, and pharmacological strategies for the inhibition of nerve growth factor

Nerve growth factor (NGF) is critical for the development and maintenance of sympathetic and sensory neurons in the developing nervous system, including nociceptors. In the adult nervous system, NGF is known to produce significant pain signals by binding to the TrkA and p75NTR receptors. Several pathological pain disorders are associated with nerve growth factor dysregulation, including neuropathic pain, osteoarthritic pain, and hyperalgesia. Currently, clinical management of these pathologies has relied on the use of opioid and non-steroidal anti-inflammatory drugs (NSAID). However, several chronic pain conditions demonstrate insensitivity to NSAID treatment or the development of detrimental opioid-related side effects, including addiction. As NGF plays an important role in pain generation; antibodies, small molecules and peptides have been designed to antagonize NGF. In this review, we discuss the structural biology of NGF ligand/receptor interaction, and we review current biological and pharmacological strategies to modulate NGF-related pathologies.     

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.     

Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoid/endovanilloid system

Neuropathic pain refers to chronic pain that results from injury to the nervous system. The mechanisms involved in neuropathic pain are complex and involve both peripheral and central phenomena. Although numerous pharmacological agents are available for the treatment of neuropathic pain, definitive drug therapy has remained elusive. Recent drug discovery efforts have identified an original neurobiological approach to the pathophysiology of neuropathic pain. The development of innovative pharmacological strategies has led to the identification of new promising pharmacological targets, including glutamate antagonists, microglia inhibitors and, interestingly, endogenous ligands of cannabinoids and the transient receptor potential vanilloid type 1 (TRPV1). Endocannabinoids (ECs), endovanilloids and the enzymes that regulate their metabolism represent promising pharmacological targets for the development of a successful pain treatment. This review is an update of the relationship between cannabinoid receptors (CB1) and TRPV1 channels and their possible implications for neuropathic pain. The data are focused on endogenous spinal mechanisms of pain control by anandamide, and the current and emerging pharmacotherapeutic approaches that benefit from the pharmacological modulation of spinal EC and/or endovanilloid systems under chronic pain conditions will be discussed.     

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.