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Dorsal root ganglia, sodium channels, and fibromyalgia sympathetic pain
Abstract
Fibromyalgia (FM) is the most frequent cause of generalized pain in the community. Trauma and infection are frequent FM triggering events. A consistent line of investigation suggests that autonomic dysfunction may explain the multi-system features of FM, and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG) are potential sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7) act as molecular gatekeepers of pain detection at peripheral nociceptors. Different infecting agents may lie dormant in DGR. Trauma or infection can induce neuroplasticity with an over-expression of sympathetic fibers and sodium channels in DRG. Nerve growth factor (NGF) mediates these phenotypic changes, which enable catecholamines and/or sympathetic impulses to activate nociceptors. Several DRG sodium "channelopathies" have been recently associated to rare painful-dysautonomic syndromes, such as primary erythermalgia and paroxysmal extreme pain disorder (formerly familial rectal pain syndrome). We propose that enhanced DRG excitability may play a key role in FM pain. Individuals at risk would be those with genetically determined sympathetic hyperactivity, or those with inherent sodium channelopathies. Today's stressful environment may contribute to permanent sympathetic hyperactivity. Trauma or infection would induce sodium channels up-regulation and sympathetic sprouting in DRG through NGF over-expression. High levels of NGF have been reported in the cerebro-spinal fluid of FM patients. These post-traumatic (or post-infective) phenotypic changes would induce a sympathetically maintained neuropathic pain syndrome resulting in widespread pain, allodynia and paresthesias - precisely, the key clinical features of FM. If this hypothesis proves to be true, then sodium channel blockers could become therapeutic options for FM pain.
... Stressresponse system malfunction would explain insomnia, fatigue, anxiety, bowel and bladder dysfunction, among other fibromyalgia symptoms (26). We have proposed that the dorsal root ganglia lying along the spinal column play a key role in fibromyalgia pain (27): in this site, stressful events of various kinds could be transformed into chronic pain. Physical (28), chemical (29) or environmental stressors (30,31) are converted into abnormal biochemical and electric impulses altering the dorsal root ganglia structure. ...
... The dorsal root ganglia sodium channels, named Nav1.7, play a major role in pain sensitisation (27). Severe fibromyalgia is associated to certain Nav1.7 genotypes (32). ...
... Non-invasive confocal microscopy of the eye cornea also shows small nerve fibre pathology in fibromyalgia (35). These new findings confirm the long-standing proposal of fibromyalgia as a neuropathic pain syndrome (36,37), and the role of dorsal root ganglia in fibromyalgia pathogenesis (27). Furthermore, these recent objective findings corroborate fibromyalgia pain veracity. ...
Somatic symptom disorder is excessive anxiety towards persistent symptoms that do not have an identifiable physical origin. Fibromyalgia is a stress-related illness. The overwhelming majority of fibromyalgia patients seeking medical care are women. Most fibromyalgia sufferers fulfil the somatic symptom disorder diagnostic criteria. The objectives of this article are the following: 1) to examine fibromyalgia and somatic symptom disorder analogy. 2) to discuss stress-evoked neuropathic pain sexual dimorphism, and 3) to propose a neuropathic pathogenesis that may explain how stressed women could develop fibromyalgia. Recent research demonstrates a clear link between fibromyalgia and small fibre neuropathy. Dorsal root ganglia contain the small nerve fibre nuclei. In rodents, physical, chemical, or environmental stressors lead to dorsal root ganglia phenotypic changes and to hyperalgesia. This phenomenon is much more frequent in females. Prolactin, oestrogens, and progesterone alter dorsal root ganglia physiology, establishing abnormal connections between the stress response system and pain pathways. Rather than a mental somatic symptom disorder, fibromyalgia patients may have a stress-induced neuropathic pain syndrome. Sexually dimorphic dorsal root ganglia physiology may explain why it is women who more often develop fibromyalgia. Understanding fibromyalgia as a real stress-evoked neuropathic pain syndrome may lead to more compassionate patient care and may open new avenues for gender-related neuropathic pain investigation.
... If FMS is interpreted in this context as a sympathetically maintained neuropathic pain syndrome, sodium-channel blockers gain importance as a therapeutic option for FMS pain. 196 At least, the sodium channel Na v 1.8, which is selectively blocked by ambroxol, is of importance in the sympathetic nervous system. Schofield et al 197 demonstrated that Na v 1.8 occurs on the sympathetic superior cervical ganglion and can be blocked. ...
... 26 The receptor is assumed to play an important role in pain transmission in DRG neurons in FMS. 196 Na v 1.7 subtypes, 170,230-233 as well as Na v 1.8 mutations, 171,234 are also associated with small-fiber neuropathy, and at least one small-fiber pathology appears to be present in a subgroup of FMS. 159,160 Although there have been reports of Na v 1.7 gainof-function mutations and even more evidently hypothalamic dysfunction, it is not known whether or not this channel subtype plays a functional role in the hypothalamus with regard to external stressors in man. ...
... Important 26,196,333 Sodium-channel blockade 34-36 Na v 1.7 ...
Fibromyalgia appears to present in subgroups with regard to biological pain induction, with primarily inflammatory, neuropathic/neurodegenerative, sympathetic, oxidative, nitrosative, or muscular factors and/or central sensitization. Recent research has also discussed glial activation or interrupted dopaminergic neurotransmission, as well as increased skin mast cells and mitochondrial dysfunction. Therapy is difficult, and the treatment options used so far mostly just have the potential to address only one of these aspects. As ambroxol addresses all of them in a single substance and furthermore also reduces visceral hypersensitivity, in fibromyalgia existing as irritable bowel syndrome or chronic bladder pain, it should be systematically investigated for this purpose. Encouraged by first clinical observations of two working groups using topical or oral ambroxol for fibromyalgia treatments, the present paper outlines the scientific argument for this approach by looking at each of the aforementioned aspects of this complex disease and summarizes putative modes of action of ambroxol. Nevertheless, at this point the evidence basis for ambroxol is not strong enough for clinical recommendation.
... The background information leading to the present investigation has been already published as a hypothesis [1] and is summarized here: A consistent line of investigation suggests that autonomic nervous system dysfunction may explain the multi-system features of fibromyalgia (FM); and that FM is a sympathetically maintained neuropathic pain syndrome. Trauma and infection are two recognized FM triggers. ...
... Trauma and infection are two recognized FM triggers. In animal models; trauma or infection can induce phenotypic changes in the dorsal root ganglia (DRG) leading to a persistent sympathetically-maintained pain state [1]. DRG are nodules that lie along the spinal column. ...
... Sodium channels play a pivotal role in this hyperexcitability. These mechanisms are the basis of the sympathetically-maintained pain concept [1]. Sodium channels located in DRG act as molecular gatekeepers of pain detection at peripheral nociceptors. ...
A consistent line of investigation suggests that autonomic nervous system dysfunction may explain the multi-system features of fibromyalgia (FM); and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG) are key sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7) act as molecular gatekeepers for pain detection. Nav1.7 is encoded in gene SCN9A of chromosome 2q24.3 and is predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons. Several SCN9A sodium channelopathies have been recognized as the cause of rare painful dysautonomic syndromes such as paroxysmal extreme pain disorder and primary erythromelalgia. The aim of this study was to search for an association between fibromyalgia and several SCN9A sodium channels gene polymorphisms.
We studied 73 Mexican women suffering from FM and 48 age-matched women who considered themselves healthy. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Genomic DNA from whole blood containing EDTA was extracted by standard techniques. The following SCN9A single-nucleotide polymorphisms (SNP) were determined by 5' exonuclease TaqMan assays: rs4371369; rs4387806; rs4453709; rs4597545; rs6746030; rs6754031; rs7607967; rs12620053; rs12994338; and rs13017637.
The frequency of the rs6754031 polymorphism was significantly different in both groups (P = 0.036) mostly due to an absence of the GG genotype in controls. Interestingly; patients with this rs6754031 GG genotype had higher FIQ scores (median = 80; percentile 25/75 = 69/88) than patients with the GT genotype (median = 63; percentile 25/75 = 58/73; P = 0.002) and the TT genotype (median = 71; percentile 25/75 = 64/77; P = 0.001).
In this ethnic group; a disabling form of FM is associated to a particular SCN9A sodium channel gene variant. These preliminary results raise the possibility that some patients with severe FM may have a dorsal root ganglia sodium channelopathy.
... In the CNS, the COMT gene modulates the production of catecholamines and other neurotransmitters that bind to adrenergic receptors, some of them modulated by the ADRA1A gene in the sympathetic nervous system. The dorsal root ganglia may be a player in sympathetically maintaining pain in FM [48]. One hypothesis is that mutations in the SCN9A gene may lead to up-regulation of sodium channels, which drives hyperexcitability of the dorsal root ganglia and, finally, leads to increased pain [48]. ...
... The dorsal root ganglia may be a player in sympathetically maintaining pain in FM [48]. One hypothesis is that mutations in the SCN9A gene may lead to up-regulation of sodium channels, which drives hyperexcitability of the dorsal root ganglia and, finally, leads to increased pain [48]. Other potential mechanisms involved in FM are pain oxidative stress [49] and excessive autophagy [50], where the CHMP1A gene may play a role [51] via amygdala [49] and mTOR signalling [52] pathways. ...
Objectives
It is widely acknowledged that the experience of pain is promoted by both genetic susceptibility and environmental factors such as engaging in physical activity (PA) and that pain-related cognitions are also important. Thus, the purpose of the present study was to test the association of 64 polymorphisms (34 candidate-genes) and the gene-gene, gene-PA, and gene-sedentary behaviour interactions with pain and pain-related cognitions in women with fibromyalgia.
Methods
Saliva samples from 274 women with fibromyalgia (aged 51.7 ± 7.7 years) were collected for extracting DNA. We measured PA and sedentary behaviour by accelerometers for a week, pain with algometry and questionnaires, and pain-related cognitions with questionnaires. To assess the robustness of the results, a meta-analysis was also performed.
Results
The rs6311 and rs6313 polymorphisms (HTR2A) were individually related to algometer scores. The interaction of rs4818 (COMT) and rs1799971 (OPRM1) was related to pain catastrophizing. Five gene-behaviour interactions were significant: the interactions of sedentary behaviour with rs1383914 (ADR1A), rs6860 (CHMP1A), rs4680 (COMT), rs165599 (COMT) and rs12994338 (SCN9A) on bodily pain subscale of the SF-36. Furthermore, the meta-analysis showed an association between rs4680 (COMT) and severity of fibromyalgia symptoms (codominant model, p-value: 0.032).
Conclusion
The HTR2A gene (individually), COMT and OPRM1 gene-gene interaction, and the interactions of sedentary behaviour with ADRA1A, CHMP1A, COMT, and SCN9A genes were associated with pain-related outcomes. Collectively, findings from the present study indicate a modest contribution of genetics and gene-sedentary behaviour interaction to pain and pain catastrophizing in women with fibromyalgia. Future research should examine whether reducing sedentary behaviour is particularly beneficial for reducing pain in women with genetic susceptibility to pain.
... In the CNS, the COMT gene modulates the production of catecholamines and other neurotransmitters that bind to adrenergic receptors, some of them modulated by the ADRA1A gene in the sympathetic nervous system. The dorsal root ganglia may be a player in sympathetically maintaining pain in FM [48]. One hypothesis is that mutations in the SCN9A gene may lead to up-regulation of sodium channels, which drives hyperexcitability of the dorsal root ganglia and, finally, leads to increased pain [48]. ...
... The dorsal root ganglia may be a player in sympathetically maintaining pain in FM [48]. One hypothesis is that mutations in the SCN9A gene may lead to up-regulation of sodium channels, which drives hyperexcitability of the dorsal root ganglia and, finally, leads to increased pain [48]. Other potential mechanisms involved in FM are pain oxidative stress [49] and excessive autophagy [50], where the CHMP1A gene may play a role [51] via amygdala [49] and mTOR signalling [52] pathways. ...
Objectives
It is widely acknowledged that the experience of pain is promoted by both genetic susceptibility and environmental factors such as engaging in physical activity (PA) and that pain-related cognitions are also important. Thus, the purpose of the present study was to test the association of 64 polymorphisms (34 candidate-genes) and the gene-gene, gene-PA, and gene-sedentary behaviour interactions with pain and pain-related cognitions in women with fibromyalgia.
Methods
Saliva samples from 274 women with fibromyalgia (aged 51.7 ± 7.7 years) were collected for extracting DNA. We measured PA and sedentary behaviour by accelerometers for a week, pain with algometry and questionnaires, and pain-related cognitions with questionnaires. To assess the robustness of the results, a meta-analysis was also performed.
Results
The rs6311 and rs6313 polymorphisms (HTR2A) were individually related to algometer scores. The interaction of rs4818 (COMT) and rs1799971 (OPRM1) was related to pain catastrophizing. Five gene-behaviour interactions were significant: the interactions of sedentary behaviour with rs1383914 (ADR1A), rs6860 (CHMP1A), rs4680 (COMT), rs165599 (COMT) and rs12994338 (SCN9A) on bodily pain subscale of the SF-36. Furthermore, the meta-analysis showed an association between rs4680 (COMT) and severity of fibromyalgia symptoms (codominant model, p-value: 0.032).
Conclusion
The HTR2A gene (individually), COMT and OPRM1 gene-gene interaction, and the interactions of sedentary behaviour with ADRA1A, CHMP1A, COMT, and SCN9A genes were associated with pain-related outcomes. Collectively, findings from the present study indicate a modest contribution of genetics and gene-sedentary behaviour interaction to pain and pain catastrophizing in women with fibromyalgia. Future research should examine whether reducing sedentary behaviour is particularly beneficial for reducing pain in women with genetic susceptibility to pain.
... Mutations of the SCN9A gene may be related to upregulation of the sodium channels and, consequently, to hyperreactivity to nociceptive stimulus [9]. ...
... It is widely accepted that a chronically sensitive central nervous system is part of the pathology of fibromyalgia [5,44]. It has been hypothesized that the dorsal root ganglion may also be hypersensitive to pain stimuli [9]. In the present study, we found that among the rs4453709 genotype (SCN9A gene), AT carriers reported the highest reduced motivation and AA carriers reported the lowest reduced activity. ...
Fatigue is a cardinal symptom in fibromyalgia. Fatigue is assumed to be the result of genetic susceptibility and environmental factors. We aimed at examining the role of genetic susceptibility for fatigue in southern Spanish women with fibromyalgia, by looking at single nucleotide polymorphisms in 34 fibromyalgia candidate-genes, at the interactions between genes, and at the gene-physical activity interactions. We extracted DNA from saliva of 276 fibromyalgia women to analyze gene-polymorphisms. Accelerometers registered physical activity and sedentary behavior. Fatigue was assessed with the Multidimensional Fatigue Inventory. Based on the Bonferroni’s and False Discovery Rate values, we found that the genotype of the rs4453709 polymorphism (sodium channel protein type 9 subunit alpha, SCN9A, gene) was related to reduced motivation (AT carriers showed the highest reduced motivation) and reduced activity (AA carriers showed the lowest reduced activity). Carriers of the heterozygous genotype of the rs1801133 (methylene tetrahydrofolate reductase, MTHFR, gene) or rs4597545 (SCN9A gene) polymorphisms who were physically active reported lower scores on fatigue compared to their inactive counterparts. Highly sedentary carriers of the homozygous genotype of the rs7607967 polymorphism (AA/GG genotype; SCN9A gene) presented more reduced activity (a dimension of fatigue) than those with lower levels of sedentary behavior. Collectively, findings from the present study suggest that the contribution of genetics and gene-physical activity interaction to fatigue in fibromyalgia is modest.
... Previous publications from our department discussed the potential role of DRG sodium channels in fibromyalgia pain [4,5]. The objective of this communication is to examine DRG unique pro-nociceptive anatomy, physiology, and immune competence, as well as to analyze recent clinical and experimental evidence linking DRG physiopathology to fibromyalgia pain. ...
... Unfolding clinical evidence favoring dorsal root ganglia involvement in fibromyalgia and similar maladies Several lines of investigation link DRG dysfunction to fibromyalgia and ME/CFS development. We described the association of DRG Nav1.7 rs6754031 GG genotype with severe fibromyalgia [4,5]. In a different study, we learned that fibromyalgia patients have norepinephrine-evoked pain [18]. ...
This perspective article focuses on dorsal root ganglia (DRG) as potential fibromyalgia main pain source. Humans possess 31 pairs of DRG lying along the spine. These ganglia have unique anatomical and physiological features. During development, DRG are extruded from the central nervous system and from the blood-brain barrier but remain surrounded by meningeal layers and by cerebrospinal fluid. DRG house the pain-transmitting small nerve fiber nuclei; each individual nucleus is tightly enveloped by metabolically active glial cells. DRG possess multiple inflammatory/pro-nociceptive molecules including ion channels, neuropeptides, lymphocytes, and macrophages. DRG neurons have pseudo-unipolar structure making them able to generate pain signals; additionally, they can sequester antigen-specific antibodies thus inducing immune-mediated hyperalgesia. In rodents, diverse physical and/or environmental stressors induce DRG phenotypic changes and hyperalgesia. Unfolding clinical evidence links DRG pathology to fibromyalgia and similar syndromes. Severe fibromyalgia is associated to particular DRG ion channel genotype. Myalgic encephalomyelitis patients with comorbid fibromyalgia have exercise-induced DRG pro-nociceptive molecules gene overexpression. Skin biopsy demonstrates small nerve fiber pathology in approximately half of fibromyalgia patients. A confocal microscopy study of fibromyalgia patients disclosed strong correlation between corneal denervation and small fiber neuropathy symptom burden. DRG may be fibromyalgia neural hub where different stressors can be transformed in neuropathic pain. Novel neuroimaging technology and postmortem inquest may better define DRG involvement in fibromyalgia and similar maladies. DRG pro-nociceptive molecules are attractive fibromyalgia therapeutic targets.
... encoded in gene SCN9A of chromosome 2q24.3 is predominantly expressed in the dorsal root ganglia pain-sensing neurons and sympathetic ganglia neurons. Different Nav1.7 mutations induce electrical hyperactivity of sensory neurons in dorsal root ganglia and; at the same time; produce hypo-reactivity of sympathetic ganglia neurons [23]. ...
... As already stated, fibromyalgia is clearly a stress-related disorder. We propose that in susceptible individuals, chronic hyper-adrenergic state may lead to neuropathic pain via dorsal root ganglia hyper-excitability [23]. The recognition of small fiber neuropathy in fibromyalgia reinforces the long-held view of fibromyalgia as a dysautonomia-connected neuropathic pain syndrome. ...
Several groups of investigators have described the presence of small fiber neuropathy in fibromyalgia patients. This writing discusses how this new finding could renovate fibromyalgia concept, diagnosis, and treatment. Predominant rheumatology thinking proposes fibromyalgia as a “centralized pain syndrome.” An alternative hypothesis views fibromyalgia as a stress-related dysautonomia with neuropathic pain features. Dorsal root ganglia may be the key autonomic-nociceptive short-circuit sites. The recent recognition of small fiber neuropathy in a large subgroup of fibromyalgia patients reinforces the dysautonomia-neuropathic hypothesis and validates fibromyalgia pain. These new findings support fibromyalgia as a primarily neurological entity, nevertheless, rheumatologist will likely remain the best equipped specialist to diagnose fibromyalgia and differentiate it from other multi-symptomatic rheumatic syndromes. Skin biopsy and corneal confocal microscopy will probably become useful fibromyalgia diagnostic tests. Dorsal root ganglia sodium channel blockers are potential fibromyalgia analgesic medications. Subgroups of young girls with “autoimmune neuropathic fibromyalgia” may respond to immunoglobulin therapy. Multimodal intervention directed to regain autonomic nervous system resilience will likely remain the cornerstone for fibromyalgia therapy.
... A single Nav1.7 mutation (L858H) induces electrical hyperactivity of sensory neurons in dorsal root ganglia and, at the same time, produces hyporeactivity of sympathetic ganglia neurons. Several sodium "channelopathies" have been associated to rare painful dysautonomic syndromes such as primary erythermalgia and paroxysmal extreme pain disorder (formerly familial rectal pain syndrome) [18]. ...
... Currently available sodium channel blockers are weak and nonspecific. Selective tetrodotoxin-resistant channel blockers are being developed and may in the future constitute an important therapeutic option for FM pain [18]. ...
Fibromyalgia is a painful stress-related disorder. A key issue in fibromyalgia research is to investigate how distress could be converted into pain. The sympathetic nervous system is the main element of the stress response system. In animal models, physical trauma, infection, or distressing noise can induce abnormal connections between the sympathetic nervous system and the nociceptive system. Dorsal root ganglia sodium channels facilitate this type of sympathetic pain. Similar mechanisms may operate in fibromyalgia. Signs of sympathetic hyperactivity have been described in this condition. Genetic factors and/or distressful lifestyle may lead to this state of sympathetic hyperactivity. Trauma and infection are recognized fibromyalgia triggers. Women who suffer from fibromyalgia have catecholamine-evoked pain. Sympathetic dysfunction may also explain nonpain-related fibromyalgia symptoms. In conclusion, in fibromyalgia, distress could be converted into pain through forced hyperactivity of the sympathetic component of the stress response system.
... 11 Dorsal root ganglia (DRG) are also important autonomic-nociceptive short-circuit sites. 12 Recent genetic studies have implicated key sympathetic system elements, such as the COMT enzyme or AR, in amplified pain sensitivity. 13,14 The concept of sympathetically maintained pain has strong and ample foundations in the animal model. ...
... Several DRG sodium ''channelopathies'' have recently been associated with rare painful dysautonomic syndromes, such as primary erythermalgia and paroxysmal extreme pain disorder (formerly called familial rectal pain syndrome). 12 ...
Fibromyalgia (FM) can be conceptualized as a failed attempt of our main complex adaptive system (the autonomic nervous system) to adjust to a hostile environment. FM cannot be fully understood through the prevailing linear-reductionist medical model. Conversely, FM can be explained using the new complexity theory paradigms. Relentless sympathetic hyperactivity in FM may be a sign of allostasis. Similarly sympathetic hyporeactivity to stress may indicate allostatic load. Dorsal root ganglia have been suggested as important sympathetic-nociceptive short-circuit sites. Autonomic dysfunction also explains non-pain-related FM features. Preliminary genetic evidence supports FM's dysautonomic nature. A scientific holistic therapy is proposed to harmonize rigid complex systems and, in doing so, to help to improve FM symptoms.
... Such sympathetic dysfunction may explain poly-symptomatic characteristics and also small fiber neuropathy in FM [41]. The sympathetic sprouting via dorsal root ganglia hyper-excitability leads to neuropathic pain or small-fiber neuropathy (SFN) [28,42]. ...
Fibromyalgia (FM) is a heterogeneous condition with various mechanisms (endotype) and manifestations (phenotypes). Many worthy endeavors have been dedicated to exploring the main trajectories of FM pathogenesis, depicted as the models of FM development. The Imbalance of Threat and Soothing Systems (FITSS) model, which is an advancing psychosocial form of the “central sensitization” model, and autonomic nervous system (ANS) model, besides new discoveries of potential pathways for FM development such as autoimmunity, small fiber pathology, and gut-brain axis currently comprise all our knowledge assets about FM pathogenesis. The pathophysiology of fibromyalgia is too complex to justify with one model, one main loop of pathogenesis, and one terminator. It appears that the variable FM models could justify some phenotypes of FM. Currently, our knowledge about FM pathogenesis and trying to match the different pathways and links mimic solving a puzzle in the hands of beginners. Until unraveling many missed interconnections and formulas between numerous scrambled pieces of the FM puzzle, proposing an integrated model seems not possible. This review focuses on the main trajectories of FM pathogenesis proposed thus far and tries to illuminate the crosstalking between them. We also propose the subgrouping FM into more homogenous categories based on the endotype-phenotype characteristics. It could provide a more pragmatic approach toward understanding of the diverse network of FM pathogenesis as well as the personalized stratification of FM.
Key Points
• The disentangled nature of FM pathogenesis escapes from embracing under one integrated model.
• There appears to be no way for formulizing FM pathogenesis except the acknowledgment of the different pathways and their crosstalk explored as yet.
• Acknowledging the different endotypes/phenotypes of FM spectrum and classifying them into more homogenous groups can help to the pragmatic approach to FM.
... These sodium channels situated in the dorsal root ganglia are the gatekeepers of pain transmission from peripheral receptors. In total, nine such sodium channel subunits (Nav 1.1-Nav 1.9) have been found distributed throughout the peripheral and central nervous systems [48][49][50]. Thus, drugs targeting the mutated sodium channel can be a prospect for FM treatment [30]. ...
The World Health Organization regards chronic pain to be a public health concern. In clinical medicine, fibromyalgia (FM) is the most prevalent chronic widespread pain disease. In terms of impairment, consumption of health and social resources, and impact on primary and speciality care systems, it has reached worrisome proportions. This disease is frequently managed by primary care providers. Because of its intricacy, fibromyalgia diagnosis and treatment can be difficult.
Fibromyalgia is a controversial condition. It might appear ill-defined in comparison to other pain conditions, with no clear knowledge of pathophysiology and hence no particular targeted therapy. This invariably sparks debates and challenges. There is no obvious cut-off point that distinguishes FM from non-FM. The diagnosis of fibromyalgia has been complicated by several factors, including patients' health-seeking behaviour, symptom identification, and physician labelling of the disease.
Fibromyalgia is currently considered a centralized pain condition, according to research that has improved our understanding of its etiopathology. A multidisciplinary strategy combining pharmacological and non-pharmacological therapies based on a biopsychosocial paradigm can result in effective therapy. Cultural and psychosocial variables appear to be a recent development in fibromyalgia, and they appear to have a larger influence on physician diagnosis than severe symptom levels in FM patients. Although physicians rely on FM criteria as the only way to classify FM patients in research and clinical settings, some crucial elements of the diagnostic challenge of fibromyalgia remain unsolved - invalidation, psychosocial variables, and diverse illness manifestation are some examples.
Beyond the existing constructional scores, physicians' judgment gained in real communicative contexts with patients, appears to be the only dependable route for a more accurate diagnosis for fibromyalgia. We have performed an exhaustive review of the literature using the keywords "Fibromyalgia", "challenges" and "diagnosis" in PubMed and Google Scholar indexes up to September 2021. This article aims to examine the causes, diagnosis, and current treatment protocols of FM, as well as discuss some continuing debates and diagnostic challenges which physicians face in accurately diagnosing fibromyalgia.
... Goebel et al.'s provocative study supports our reiterated proposal of DRG as the key neural hub where different fibromyalgia-inducing stressors, including autoimmune illnesses, are converted into neuropathic pain [14,17,18]. More research is needed to define if fibromyalgia is a localized autoimmune illness. ...
... There is also sodium-channel hyperexcitability with pathological electrical activity. 10 After trauma, DRG glial cells produce diverse proinflammatory mediators including tumor necrosis factor α and interleukin 6. Perineuronal glial cells appear to play a major role in the inflammatory response. These cells have diverse cytokine receptors and upon stimulation are able to release glutamate. ...
Background:
Spread of complex regional pain syndrome (CRPS) outside the affected limb is a well-recognized phenomenon; nevertheless, the actual evolution from CRPS to fibromyalgia is poorly documented. Similar mechanisms have been recently put forward to explain the development of CRPS and fibromyalgia including dorsal root ganglia (DRG) hyperexcitability and small fiber neuropathy.
Objectives:
The aims of this study were to describe 3 cases with typical CRPS evolving to full-blown fibromyalgia and to discuss the potential pathogenetic mechanisms linking these debilitating illnesses.
Methods:
This was a review of medical records and PubMed search on the relationship between CRPS-fibromyalgia with DRG and small nerve fiber neuropathy.
Results:
Our 3 cases displayed over time orderly evolution from CRPS to fibromyalgia. Dorsal root ganglion hyperexcitability and small fiber neuropathy have been recently demonstrated in CRPS and in fibromyalgia. Dorsal root ganglia contain the small nerve fiber cell bodies surrounded by glial cells. After trauma, DRG perineuronal glial cells produce diverse proinflammatory mediators. Macrophages, lymphocytes, and satellite glial cells may drive the immune response to more rostrally and caudally located DRG and other spinal cord sites. Dorsal root ganglion metabolic changes may lead to small nerve fiber degeneration. This mechanism may explain the development of widespread pain and autonomic dysfunction.
Conclusions:
Clinicians should be aware that CRPS can evolve to full-blown fibromyalgia. Spreading of neuroinflammation through DRG glial cell activation could theoretically explain the transformation from regional to generalized complex pain syndrome.
... Another mechanism by which thermoceptive neurons become hyperalgesic is through exposure to nerve growth factor (NGF) secreted from mast cells. While it is appreciated that NGF has a critical role in the development of peripheral neurons (Depp- mann et al., 2008), when neurons are re-exposed to it in adulthood, it causes intense pain (Martinez-Lavin and Solano, 2009). NGF-TrkA activation leads to phosphorylation and sensitisation of the transient receptor potential vanilloid receptor 1(TrpV1), which is responsible for detecting radiant heat and capsaicin, the active compound in chilli peppers (Figure 4) (Galoyan et al., 2003). ...
Wound healing is critical for normal tissue function and the survival of most multicellular organisms. Understanding the biochemical and cellular mechanisms underlying constructive physiological wound healing is crucial for developing therapies to aid in repair and regeneration. Wound healing involves multiple systems including blood, vasculature, somatosensory, immune system and the skin. Following vascular damage, coagulation system activation occurs resulting in clot formation and cell signalling events in both cells of the vasculature (e.g. endothelial cells) as well as circulating cells (e.g. platelets, leukocytes) in order to drive cessation of blood loss. Pain signalling is initiated in part by surrounding inflammatory cues and is used to prevent further damage to the wound. Following these initial responses to the wound, healing/regeneration returns the damaged tissue to a functional state. This occurs by engaging the fibrin network to create a new microenvironment architecture. A broad overview is presented of how the different organ systems are integrated to repair tissue after a wound.
Key Concepts
Blood coagulation is driven by exposure of the subendothelial receptor tissue factor that drives activation of downstream clotting factors, including activation of the central protease thrombin. Platelet activation is mediated by thrombin cleavage of cell surface protease‐activated receptors, tight receptor‐mediated binding to collagen or activation of the purinergic receptors (i.e. P2Y1, P2Y12). In addition to platelet activation, thrombin catalyses the conversion of fibrinogen into fibrin, the primary structural component of the blood clot.
Immune cells like mast cells and macrophages are recruited and activated once a wound occurs, releasing cytokines and histamine. This inflammatory response aids in promoting pain signalling and eventually aids in the wound healing process.
In response to the wound and release of inflammatory factors (e.g. cytokines, histamine, bradykinin, NGF and PGE2) sensory neurons become hypersensitive. This hypersensitisation (hyperalgesia) leads to innocuous tactile information to be interpreted as painful by both the peripheral nervous system (PNS) and central nervous system (CNS).
Numerous stem cell populations derived from the dermis and hair follicle contribute to wound remodelling. These stem cells differentiate into cell types like myofibroblasts, which either repopulate the site of the wound and/or deposit new extracellular matrix proteins to form a fibrotic scar.
A balance between Wnt and TGF‐β signalling guides regenerative and healing processes, respectively. Wnt signalling leads to cell proliferation and the reappearance of hair follicles inducing wounds to heal without a scar. TGF‐β signalling induces reticular dermis stem cells to differentiate into myofibroblasts, which leads to scar tissue.
... More specifically, researchers have documented that prolonged DRG stimulation -such as occurs with inflammation, trauma or infection can precipitate neuroplasticity in the form of sympathetic-somatic short circuits. These short circuits are initiated when an insulted or activated DRG releases nerve growth factors which in turn stimulate sprouting of local sympathetic neurons back into the activated DRG [10]. As such, isolated dysfunction at the DRG/DH not only impacts the central and peripheral nervous systems but can simultaneously interfere with the autonomic nervous system, further supporting the DRG/DH as a potential location for the pathology underlying Fibromyalgia. ...
Fibromyalgia is a chronic and disabling neurological disease that impacts 2 to 8% of the population. The disease has long been a medical enigma and it wasn't until this millennium that it was correctly defined as a Neurological condition. Even today our understanding of Fibromyalgia is in its infancy as the neural pathways and pain generators responsible for the symptoms remain elusive. At this point, it seems reasonable to describe our efforts to unlock the mysteries of Fibromyalgia based upon our current understanding of the nervous system as disappointing. As such, it may be reasonable to start considering "outside of the box" thinking in regards to even basic Neurological concepts moving forward. This "outside of the box" thinking seems to especially make sense in regards to investigating a neurological disease that causes inexplicable or "non-physiological" symptoms. The following case series introduces the Referred Sympathetic Pain Map (MAP) and Fibromatome concepts. These descriptions fall "outside of the box" in regards to basic Neuroanatomy and Neurophysiology. However, they otherwise seem to be consistent with and supported by contemporary research in Fibromyalgia and pain management. In addition, these concepts were discovered based on changes in pre versus post-procedural pain maps following selective nerve root procedures-a gold standard diagnostic method. Also, the MAP provides a physiological explanation for seemingly inexplicable pain patterns amongst Fibromyalgia and other chronic pain patients; and the MAP, which was initially described in 2010, was probably the first report of an intervention at the DRG for sympathetically mediated symptoms-a treatment for CRPS now in clinical use. The Referred Sympathetic Pain Map (MAP) is analogous to the Dermatomal Map in regards to the manner that it is comprised of individual dermatomes. More specifically the MAP is composed of 14 individual Fibromatomes, each of which represents a spinal level between T1 and L2 that innervates a specific body region. However, unlike the Dermatomal Map, the Referred Sympathetic Pain Map is only applicable to individuals with Fibromyalgia and undefined chronic pain-theoretically, those who have developed aberrant sympathetic-somatic short circuits due to neuroinflammation. Each Fibromatomes from the T1 to L2 level is described for the sake of completeness. However, case reports for the T1 through T3 and the T12 through L2 levels are not included because they are not well defined or understood by the authors. On the other hand, the T4 to T10 (and to a lesser degree T 11) levels which are described in this case study report produced consistent results in a significant percentage of patients treated. In addition, at these levels the responses were fascinating in comparison to dermatomes including most notably:-That a single level often innervated upper and lower extremities simultaneously. While this feature is inconsistent with the somatic nervous system, the embryology of the sympathetic nervous system provides potential insight for this phenomenon.-Each level seemed to primarily cause arthralgia or more widespread symptoms in the impacted regions of the extremities.-Frequently patients who described notable pain relief also described changes in other Fibromyalgia related symptoms such as fatigue and even complaints such as asthma. The authors are well aware that these concepts are unique, but as based on the descriptions above believe they are worthy of further evaluation with well designed clinical studies. If such studies document the MAP, it could potentially impact the clinical treatment of chronic pain patients with poorly understood complaints and provide meaningful information for basic scientists working to unlock the Fibromyalgia mystery.
... Here, peripheral and central memory and sensitization processes take place that implicate the sympathetic branch . Various pathomechanisms are involved that can be influenced by local anesthesia, including, for example, the following: 2008; Martinez-Lavin and Solano, 2009;McLachlan et al., 1993;McLachlan and Hu, 2014;Price and Mudge, 1983;Ramer et al., 1999: Yen et al., 2006 • Sympathetic-afferent coupling (Baron and Jänig, 1998; Baron and Raja, 2002;Devor and Jänig, 1981;Devor et al., 1994;Jänig and Koltzenburg, 1991;Jänig and Koltzenburg, 1992;Jänig and McLachlan, 1994;Jänig et al., 1996;Schattschneider et al., 2003) • Positive neuronal feedback loops, with the sympathetic nervous system being implicated on a spinal and supraspinal level (Eggli and Fischer, 2011;Fischer, 1998;Fischer, 2003;Fischer, 2013; • Sensitization of wide dynamic range (WDR) neurons (Zieglgänsberger, 2010) • Release of pro-inflammatory neuropeptides from sympathetic fibers (Baron and Jänig, 1998;Cassuto et al., 2006;Goadsby and Edvinsson, 1993;Herbert and Holzer, 2002;Jänig, 2006;Miao et al., 1996a;Miao et al., 1996b;Strittmatter et al., 1996;van de Beek et al., 2001) • Vasomotor-related inflammation (Ricker, 1924;Jänig, 2006) • Disruption of the interaction between the sympathetic nervous system and the immune system (Elenkov et al., 2000;Hori et al., 1995;Jänig, 2006;Madden and Felten, 1995;Marvar and Harrison, 2012;Pongratz and Straub, 2010;Pongratz et al., 2012;Straub et al., 2006;Watkins et al., 2007;Yokoyama et al., 2000). ...
Background:
The sympathetic nervous system has an important role in generating pain. Various pathomechanisms are involved that respond well to the application of local anesthetics (LA), for example to the stellate ganglion block (SGB).
Objectives:
We wanted to know more about the effects of SGB on cardiovascular parameters.
Methods:
We included 15 healthy volunteers; another 15 healthy volunteers as a control group (sham injection of LA). In order to produce a more precise SGB, we employed only a small volume of LA (3mL), a LA with a lower permeability (procaine 1%), and a modified injection technique. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), and echocardiographic parameters were recorded before and after SGB. We also investigated whether there are side differences (left and right SBG).
Results:
At baseline all parameters were within the normal range. After performing right and left SGB DBP significantly increased (on the right side from 68.73±8.61 to 73.53±11.10, p=0.015; on the left side from 70.66±13.01 to 77.93±10.40, p=0.003). In the control group no increase in DBP was observed. No side-specific differences were found, except a significant reduction in the maximum velocity of myocardial contraction during the systole with left-sided SGB.
Conclusions:
Even with our methods we could not prevent the simultaneous occurrence of a partial parasympatholytic effect. For this reason, the SGB has only minor hemodynamic effects, which is desirable as it enhances the safety of the SGB.
... Nav 1.7 is found in the dorsal root and sympathetic ganglia. It is particularly highly expressed in nociceptors [9]. The effects of hyper-excitability in these areas correlate to the clinical picture. ...
Title :Paroxysmal extreme pain disorder (PEPD) is an autosomal dominant painful neuropathy with many,but not all, cases linked to gain-of-function mutations in SCN9A which encodes voltage-gated sodium channel Na.1.7. It is a very rare condition featured by flushing of the lower half of the body and excruciating burning pain caused by any stimulus below the waist or in the perianal region. PEPD may be associated with cardiovascular instability, especially prolonged sinus pauses, and thus has anesthetic implications. Pacemaker implantation is the alternative therapeutic option, but its indications have not been clarified yet.
Background: This condition is well described in neurological literature, but to our knowledge, this is the first case report of a patient with paroxysmal extreme pain disorder with prolonged sinus pauses requiring anesthesia for an epicardial pacemaker even with the peri-operative risk of the pathology.This clinical observation can help for a better management and understanding of the cardiac risk complications of PEPD especially for an infant whose diagnostic is frequently made at the stage of complication This clinical observation can put the item on the necessity of establishing recommendations for management of cardiac complications during PEPD.
Case report: We extensively searched the literature on cardiac pacing in patients with PEPD and we described a new case of a 9 month old infant who was admitted in the emergency department for an episode of malaise apnea and hemifacial cyanosis relevant to PEPD. The neurologic exploration was normal. The diagnostic was confirmed by genetic study. The 24 hours recording demonstrated long pauses of 15 seconds during the crisis justifying the implantation of epicardial pacemaker without peri-operatory complications due to the high anesthetic risk of this pathology.
Conclusion: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures. Clinicians must evocate this diagnostic even any clinical suspicion given the severity of cardiac complications.
... In this model, repeated or sustained noxious stimulation can lead to increased neuronal responsiveness or central sensitization [123], and this stimulation can cause the spinal cord to become sensitized, or placed into a "hyperexcitable" state [347]. Martinez-Lavin and Solano [348] speculate that within the dorsal root ganglia, after trauma or inflammation due to infection, sympathetic nervous system neurons gain greater long-term potentiation through up-regulated ion channels, increasing pain synapses in the dorsal root ganglia become hyperexcitable to painful inputs. In other words, patients may have a sensitized central nervous system, and if the pain inhibitory systems are not functioning adequately, the central nervous system may become hyperexcitable. ...
Myalgic Encephalomyelitis (ME) continues to cause significant morbiditiy worldwide with an estimated one million cases in the United States. Hurdles to establishing consensus to achieve accurate evaluation of patients with ME continue, fueled by poor agreement about case definitions, slow progress in development of standardized diagnostic approaches, and issues surrounding research priorities. Because there are other medical problems, such as early MS and Parkinson's Disease, which have some similar clinical presentations, it is critical to accurately diagnose ME to make a differential diagnosis. In this article, we explore and summarize advances in the physiological and neurological approaches to understanding, diagnosing, and treating ME. We identify key areas and approaches to eludicate the core and secondary symptom clusters in ME so as to provide some practical suggestions in evaluation of ME for clinicians and researchers.This review, therefore, represents a synthesis of key discussions in the literature, andhas important implications for a better understanding of ME, its biological markers, and diagnostic criteria. There is a clear need for more longitudinal studies in this area with larger data sets, which correct for multiple testing.
... Different types of channelopathies (diseases caused by disturbed function of ion channel subunits or the proteins that regulate them), all involve the same Na v 1.7 sodium channel: (1) primary erythermalgia [3][4] ; (2) paroxysmal extreme pain disorder [1] ; (3) and channelopathy-associated insensitivity to pain are typified by different pain phenotypes [5] . In an experimental model of inflammatory pain in which an irritant was injected into the hind paws of rats, Na v 1.7 protein expression was up-regulated within dorsal root ganglion neurons that project their axons to the inflamed area [6][7][8][9] . However, its role in the model of neuropathic pain remains unclear. ...
Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behavioral tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic pain rats 3-28 days following model induction. The results of immunohistochemistry, western blot assays and reverse transcription-PCR showed that Nav1.7 protein and mRNA expression was significantly increased in the injured dorsal root ganglia. These findings indicated that Nav1.7 might play an important role in the model of chronic neuropathic pain.
... 12 With fibromyalgia, trauma and infection are two recognized triggers, of which surgery is an iatrogenic trauma. 13 Medical management of NPP has improved with the arrival of effective neuroleptics including gabapentin and pregabalin. 14,15 At our institution, these medications have been routinely prescribed to patients diagnosed with postoperative NPP. ...
Neuropathic pain (NPP) following breast surgery extends morbidity in the postoperative period. The incidence and etiology of postoperative NPP remains unclear and under-reported in literature. This study aims to define the incidence of neuropathic pain following breast surgery and to identify patient characteristics that are predictors for developing postoperative NPP.
Consecutive female patients undergoing breast resection surgery over a 5-year period (2008-2012) with 1-year minimum follow-up were included in this single-center study. Retrospective chart review was performed to identify patient specific characteristics including the development of post-operative NPP. Data was analyzed using univariate and multivariate logistic regression.
A total of 470 patients were identified for study inclusion. The incidence of postoperative NPP was 14.7 % (69 of 470). Significant predictors for the development of postoperative NPP in the univariate analyses included history of diabetes mellitus, diabetic neuropathy, or fibromyalgia, concomitant axillary surgery, axillary node dissection, and taxane-based chemotherapy regimen. Multivariate analysis identified African American race [odds ratio (OR) = 1.78; 95 % CI = 1.01-3.17; p = 0.05), history of diabetes mellitus (OR = 1.98; 95 % CI = 1.0-3.74; p = 0.01) or fibromyalgia (OR = 2.75; 95 % CI = 1.13-6.69; p = 0.03), and taxane-based chemotherapy regimen (OR = 2.85; 95 % CI = 1.23-6.58; p = 0.01) as being independently associated with the development of postoperative NPP.
NPP is a significant risk following breast surgery. African American race, history of either diabetes mellitus or fibromyalgia, and treatment with taxane-based chemotherapy regimens are all associated with an increased risk of NPP.
... 22 Recent studies have focused on the role of the DRGs in the mechanisms of pain sensitivity and neurological pain. [23][24][25] In one type of peripheral neuropathy, acquired sensory ganglionopathy, the sensory nerve cell bodies in the DRGs were damaged, resulting in sensory loss in the large fibers. 26 Most of the distal axonpathies have been shown to display simultaneous distal degeneration of both the peripheral and central axons of DRGs, a condition termed central-peripheral distal axonopathy, whereas others display only selective distal degeneration of the peripheral axons. ...
Objectives:
Dorsal root ganglia (DRGs) have an important role in the peripheral mechanism of sensation by primary afferent neurons, which are widely used to research the processes of cell death, axonal regeneration, signal transmission of growth factors and the mechanism of pain.
Methods:
In the present study, we investigated the activation of autophagy in DRGs in a rat model of acute spinal cord injury at different time points.
Results:
Expression of microtubule-associated protein light chain 3, a marker of autophagy was increased after 8 h in DRGs, peaked after 3 days, and then gradually decreased after 7 days. Furthermore, the toluidine blue staining has proven that after acute spinal cord injury, the myelin sheathes of DRGs undergo histopathological changes over time, with axonal swellings, disorderly arrangement and uneven distribution.
Conclusion:
Potential treatment aimed at recovery of behavioral locomotor and sensory perception should target the process of autophagy in DRGs.
... Altered sodium channels may facilitate this pain sensitization. Sympathetic dysfunction can also explain non-pain related FM symp- toms [28]. HRV analysis is a computer-based technology, therefore , it has abundant development potentials. ...
At present, there is neither a laboratory test nor an imaging technique able to differentiate people with fibromyalgia (FM) from healthy controls. This lack of an objective biomarker has hampered FM recognition and research. Heart rate variability (HRV) analyses provide a quantitative marker of autonomic nervous system activity. Nighttime is a stable period in which most people are resting. Sleep is modulated by autonomic activity. Sleeping problems are prominent in FM. The objectives of this study are: 1) to explore different nocturnal HRV parameters as potential FM biomarkers and 2) to seek correlation between such HRV parameters and diverse FM symptoms.
We studied 22 women suffering from FM and 22 age-matched controls. All participants filled out several questionnaires related to FM symptoms. All participants used a Holter monitor over 24 hours while undertaking their routine activities during the day and while sleeping at their homes at night. Time-domain HRV parameters analyzed from 0000 to 0600 hours included, among others: mean normal-normal interbeat intervals (mean NN), standard deviation of the NN intervals (SDNN), and standard deviation of the successive NN differences (SDSD).
Nocturnal SDNN of less than 114 ms had the greatest predictive value to set apart patients from controls with an odds ratio of 13.6 (95% confidence interval: 3.9 to 47.8). In patients, decreased nighttime HRV markers indicative of sympathetic predominance had significant correlations with several FM symptoms: SDSD was associated with pain intensity (r = -0.65, P = 0.001). SDNN correlated with constipation (r = -0.53, P = 0.001), and mean NN with depression (r = -0.53, P = 0.001). Controls displayed an opposite behavior. For them, increased nighttime SDNN correlated with Fibromyalgia Impact Questionnaire scores (r = 0.69, P = 0.001) and with other FM symptoms.
Nocturnal HRV indices indicative of sympathetic predominance are significantly different in FM women when compared to healthy individuals. In FM patients, these HRV parameters correlated with several symptoms including pain severity. Opposite associations were seen in controls. FM may not be just one end of a continuous spectrum of common symptoms. Nocturnal HRV analyses are potential FM biomarkers.
... Stress may also influence sodium channels, as a stressful environment may contribute to permanent sympathetic hyperactivity which will induce sodium channel up-regulation and sympathetic sprouting in dorsal root ganglia through nerve growth factor over-expression. 47 Tricyclic anti-depressants, eg, amitriptyline, 48 and some anti-convulsants, eg, phenytoin, carbamazepine and oxcarbazepine, antagonise sodium channels. 42 Typically these drugs are first-line therapy for neuropathic pain and trigeminal neuralgia in humans. ...
Feline orofacial pain syndrome (FOPS) is a pain disorder of cats with behavioural signs of oral discomfort and tongue mutilation. This report describes the findings from a case series of 113 cats including 100 Burmese. FOPS is suspected to be a neuropathic pain disorder and the predominance within the Burmese cat breed suggests an inherited disorder, possibly involving central and/or ganglion processing of sensory trigeminal information. The disease is characterised by an episodic, typically unilateral, discomfort with pain-free intervals. The discomfort is triggered, in many cases, by mouth movements. The disease is often recurrent and with time may become unremitting - 12% of cases in this series were euthanased as a consequence of the condition. Sensitisation of trigeminal nerve endings as a consequence of oral disease or tooth eruption appears to be an important factor in the aetiology - 63% of cases had a history of oral lesions and at least 16% experienced their first sign of discomfort during eruption of permanent teeth. External factors can also influence the disease as FOPS events could be directly linked to a situation causing anxiety in 20% of cats. FOPS can be resistant to traditional analgesics and in some cases successful management required anti-convulsants with an analgesic effect.
... Many patients diagnosed with CFS are also diagnosed with fibromyalgia, a condition involving muscle pain. A theory has recently been put forth in which fibromyalgia results from trauma or infection of the sensory ganglia [57]. I speculate that the muscle pains seen in fibromyalgia may be caused, at least in some cases, by VZV infection of the sensory nerves enervating the muscles. ...
This article posits that infection of the peripheral ganglia causes at least some cases of Chronic Fatigue Syndrome (CFS), with a neurotropic herpesvirus, particularly varicella-zoster virus (VZV), as the most likely cause of the infection. Virtually all CFS symptoms could be produced by an infection of the peripheral ganglia, with infection of the autonomic ganglia causing fatigue, postural hypotension, and sleep disturbances, and infection of the sensory ganglia causing sensory symptoms such as chronic pain. Furthermore, infections of the peripheral ganglia are known to cause long-term nerve dysfunction, which would help explain the chronic course of CFS. Herpesviruses have long been suspected as the cause of CFS; this theory has recently been supported by studies showing that administering antiherpes agents causes substantial improvement in some CFS patients. VZV is known to frequently reactivate in the peripheral ganglia of previously healthy adults and cause sudden, debilitating illness, making it a likely candidate as a cause of CFS. Moreover, many of the symptoms of CFS overlap with those of herpes zoster (shingles), with the exception that painful rash is not one of the symptoms of CFS. A model is therefore proposed in which CFS is one of the many manifestations of zoster sine herpete; that is, herpes zoster without rash. Furthermore, re-exposure to VZV in the form of chickenpox has become less common in the past few decades; without such re-exposure, immunity to VZV drops, which could explain the increased incidence of CFS. Co-infection with multiple herpesviruses is a possibility, as some CFS patients show signs of infection with other herpesviruses including Epstein-Barr, Cytomegalovirus, and HHV6. These three herpesviruses can attack immune cells, and may therefore promote neurotropic herpesvirus reactivation in the ganglia. The possibility of VZV as the causal agent in CFS has previously received almost no attention; the possibility that CFS involves infection of the peripheral ganglia has likewise been largely overlooked. This suggests that the search for a viral cause of CFS has been far from exhaustive. Several antiherpes drugs are available, as is a vaccine for VZV; more research into such agents as possible treatments for CFS is urgently needed.
A prática de atividade física (AF) é amplamente
reconhecida como uma das estratégias mais eficazes
e a de menor custo para a promoção da saúde e prevenção de
doenças crônicas não transmissíveis (DCNTs) (Winpenny et all,
2020). No contexto educacional, incentivar e facilitar essa prática
é essencial, não apenas pelos benefícios físicos, mas também pelos
impactos no bem-estar mental, social e no desenvolvimento
cognitivo dos estudantes (OMS, 2022), além de projetar o hábito
saldável e benefícios a saúde para vida adulta (Winpenny et all,
2020). Entretanto, apesar dos esforços globais e nacionais, como
os programas de incentivo à AF nas escolas brasileiras, os níveis
de sedentarismo entre crianças, adolescentes e adultos jovens
continuam preocupantes, e com projeções de ampliação até 2035.
(World Obesity Federation, 2024).
Este capítulo tem como objetivo discutir os desafios e
percepções: barreiras para a prática de atividade física no contexto
educacional, divido em 5 tópicos: (1) Visão geral das políticas e
diretrizes educacionais relacionadas à atividade física no contexto
298 Entendendo os Temas Emergentes em Treinamento...
escolar; (2) Importância da prática de atividade física e barreiras
percebidas no contexto educacional; (3) Barreiras à Atividade Física
na Infância; (4) Desafios para a Prática de Atividade Física entre
Adolescentes e (5) A Prática de Atividade Física no Ensino Superior.
A fragmentação tem como objetivo discutir o cenário e principais
barreiras que limitam a prática regular de AF no ambiente escolar
e universitário, abordando os desafios enfrentados por diferentes
grupos etários, desde a infância até a fase adulta de uma forma mais
organizada. Desejamos uma excelente leitura.
Visão geral das políticas e diretrizes educacionais relacionadas
à atividade física no contexto escolar.
A educação física (EF) nas escolas é um componente
essencial da educação básica no Brasil, conforme estabelecido
na Base Nacional Comum Curricular (Brasil 2018). A educação
física une aspectos de educação e saúde, oferecendo conhecimento,
aprendizado e vivências corporais que beneficiam várias dimensões
da saúde, como a física e motora, psicológica, social e ambiental,
além da cognitiva (TOMPSETT et al., 2017). Assim, diversas
estratégias com objetivo de prática de atividades física têm sido
analisadas e colocadas em prática, relacionadas a aspectos como
política e ambiente, currículo, orientações adequadas e avaliação
dos alunos, visando promover um impacto positivo na vida e na
saúde dos estudantes (BESSA et al., 2019).
A contribuição positiva das aulas de educação física escolar
para a saúde tem sido fundamental na elaboração de recomendações
para a EF em diversos países (GARCÍA-HERMOSO et al., 2020).
Foram registrados benefícios em indicadores de saúde física e
motora, como a aptidão cardiorrespiratória e as habilidades motoras
básicas; na saúde psicológica, incluindo engajamento, motivação,
autonomia, afetividade e redução da ansiedade e depressão; e
na saúde socioambiental, destacando a empatia, a cooperação, a
formação de amizades e comportamentos pró-sociais (BESSA et
al., 2019).
Entendendo os Temas Emergentes em Treinamento... 299
A promoção da saúde se transforma em uma política
pública no Brasil, com a escola sendo um ambiente propício para
a implementação de recursos educativos voltados a esse objetivo.
Portanto, iniciativas governamentais sustentam essas estratégias no
ambiente escolar, como o Programa Saúde na Escola, Programa
Nacional de Alimentação Escolar (PNAE). O Programa Saúde na
Escola (PSE) foi criado no Brasil em 2007, por meio do Decreto
Presidencial nº 6.286, de 5 de setembro de 2007, como uma
iniciativa de política pública que integra os setores de educação e
saúde (BRASIL, 2022).
Entre as ações previstas no programa, destacam-se:
promoção da atividade física; saúde ambiental; alimentação
saudável e prevenção da obesidade; incentivo à cultura de paz e aos
direitos humanos; prevenção da violência e de acidentes; combate a
doenças negligenciadas; verificação do estado vacinal; saúde sexual
e reprodutiva, além da prevenção ao Vírus da Imunodeficiência
Humana (HIV) e a Infecções Sexualmente Transmissíveis (IST);
prevenção ao uso de álcool, tabaco e outras drogas; saúde bucal;
saúde auditiva; saúde ocular; e medidas de prevenção à Covid-19,
incorporadas em julho de 2020 (BRASIL, 2022).
Em relação à promoção da atividade física, a literatura
científica destaca os benefícios dessa prática para a saúde de indivíduos
de todas as idades. Para crianças e jovens, os efeitos positivos estão
associados a diversos aspectos, como o desenvolvimento humano,
a melhoria da socialização, a saúde cardiovascular e a condição
física. Além disso (BRASIL, 2021). Para esse grupo, a prática de
atividade física auxilia no desenvolvimento de habilidades motoras,
melhora o humor, reduz a sensação de estresse, ajuda a manter um
peso corporal saudável e contribui para um melhor desempenho
escolar. É importante ressaltar que o PSE abrange estudantes de
todos os níveis de ensino, desde a creche até a educação de jovens
e adultos, com a maioria dos participantes sendo alunos do Ensino
Fundamental (BRASIL, 2021)
O PSE promove ações intersetoriais e mobiliza parceiros
na rede de atenção básica à saúde e no ensino fundamental
300 Entendendo os Temas Emergentes em Treinamento...
público, visando aprimorar o cuidado individual e coletivo, além
de reduzir riscos e agravos que afetam crianças e adolescentes. O
objetivo é ampliar os mecanismos de enfrentamento e garantir um
cuidado integral. Desde sua implementação, o PSE tem registrado
avanços significativos, mas também enfrenta importantes desafios.
Sua agenda de adesões, expandida nos marcos regulatórios, é
frequentemente debatida no contexto das interconexões entre os
setores.
Já o Programa Nacional de Alimentação Escolar (PNAE),
criado em 1995 e inicialmente denominado “Campanha de
Merenda Escolar”, é uma das políticas públicas mais antigas
do Brasil e um dos maiores programas de alimentação escolar
do mundo. (PEDRAZA et al., 2018). O PNAE tem como
principal objetivo garantir aos estudantes uma alimentação digna,
assegurando pelo menos uma nutrição segura e de qualidade. Com
o programa, todos os alunos matriculados na educação básica,
incluindo as etapas de educação infantil (creche e pré-escola),
ensino fundamental e ensino médio, são atendidos. Além disso,
o PNAE beneficia também estudantes indígenas, quilombolas,
aqueles que recebem Atendimento Educacional Especializado
(AEE), e os matriculados na Educação de Jovens e Adultos (EJA)
em escolas públicas, filantrópicas, conveniadas com o poder público
e instituições confessionais, assim como nas escolas federais. Esses
estabelecimentos recebem recursos financeiros da União por meio
do Fundo Nacional de Desenvolvimento da Educação (FNDE)
(FERREIRA et al., 2019).
Diante desse contexto, é fundamental promover ações e
políticas que incentivem a atividade física nas escolas, especialmente
aquelas ligadas à Atenção Primária à Saúde (APS), que é o foco de
atuação do PSE. Isso visa encorajar sistemas, sociedades e indivíduos
a se tornarem mais ativos. Também é essencial capacitar gestores e
profissionais de educação e saúde com documentos orientadores,
como o “Guia de Atividade Física para a População Brasileira”,
as Recomendações para Gestores e Profissionais de Saúde e os
Cadernos Temáticos do PSE, elaborados pela gestão federal, que
Entendendo os Temas Emergentes em Treinamento... 301
têm como um de seus objetivos estimular a oferta de práticas de
atividade física nas escolas.
Importância da prática de atividade física e barreiras
percebidas no contexto educacional.
É fundamentado na literatura que a prática de atividade
física (AF) traz inúmeros benefícios; estes estão alinhados ao
conceito de saúde, abrangendo aspectos físicos, sociais e psicológicos
(OMS, 2022). Nessa perspectiva, a adoção de ferramentas para
identificação frente essa problemática, tornam-se imprescindíveis.
A avaliação das barreiras percebidas é crucial, pois, referem-se às
dificuldades subjetivas percebidas por indivíduos que podem
impedir ou desencorajar a adoção de comportamentos saudáveis,
como a prática de AF.
A prática regular de AF desempenha um papel crucial
na prevenção e controle de complicações relacionadas às doenças
crônicas não transmissíveis (DCNT), responsáveis por 41
milhões de mortes anualmente em todo o mundo (OMS, 2023)
Adicionalmente, prejuízos ao erário público na ordem de 1,14
bilhão/ano, somente no Brasil (Bielemann, 2010).
Neste sentido, múltiplos esforços estão sendo realizados
para ampliar os níveis de AF nos diversos públicos, em especial
para pessoas mais jovens, onde os impactos precoces, são focos
de maiores discussões. No entanto, mesmo com as ações e metas
estabelecidas, parece que elas não estão produzindo os resultados
esperados. (World Obesity Federation, 2024).
Nessa perspectiva, a adoção de ferramentas para identificação
frente essa problemática, tornam-se imprescindíveis. A avaliação
das barreiras percebidas é crucial, pois, referem-se às dificuldades
subjetivas percebidas por indivíduos que podem impedir ou
desencorajar a adoção de comportamentos saudáveis, como a
prática de AF (ref ). Essas barreiras podem incluir fatores pessoais,
como falta de motivação, baixa autoestima e dificuldade de gestão
302 Entendendo os Temas Emergentes em Treinamento...
do tempo, que têm sido identificadas como as principais barreiras
(Rigoni, 2012; Sousa, 2010). É crucial compreender que a falta
de tempo não é meramente uma desculpa, mas sim um reflexo
das dificuldades organizacionais enfrentadas por muitos adultos
em equilibrar suas atividades diárias (Rech et al., 2018)., barreiras
ambientais, como a ausência de espaços adequados para a prática
de exercícios (Sousa, 2010), além de barreiras sociais, como a falta
de apoio de amigos e familiares, e econômicas, como a dificuldade
de acesso a academias ou equipamentos, que influenciam a decisão
e a capacidade de se engajar regularmente em atividades físicas.
Eventos e transições ao longo da vida exercem um impacto
negativo significativo sobre a AF e outros comportamentos de
estilo de vida (Winpenny et al., 2020), o que representa um desafio
adicional para a manutenção de hábitos saudáveis durante períodos
de mudança, particularmente entre os universitários (Ferreira Silva
et al., 2022). Evidências indicam uma diminuição na AF durante
a transição da adolescência para a idade adulta, com uma redução
média de 5,2 minutos por dia de atividade física de intensidade
moderada a vigorosa (Corder et al., 2019). Assim, o objetivo
do escopo do capítulo é discorrer sobre os desafios e percepções
enfrentadas pelas por esse segmento da população no percurso
formativo da educação básica e superior
Barreiras percebidas à prática de AF entre universitários
podem ser atribuídas a diversas dimensões, incluindo fatores
psicológicos, emocionais, cognitivos, ambientais, socioeconômicos
e demográficos, como falta de tempo, motivação, acessibilidade
a locais apropriados e limitações financeiras (Ferreira Silva et
al., 2022). Este estudo visa explorar e quantificar essas barreiras
específicas para a prática de AF no lazer entre estudantes
universitários, proporcionando uma compreensão mais profunda
dos fatores que influenciam seus comportamentos de saúde.
Neuropathic pain has become an intractable health threat, with its profound effect on quality of life. Dorsal root ganglia (DRG) is evidenced to play a crucial role in neuropathic pain. The peripheral nociceptive afferents seem to be essential not only to initiate the process of neuropathic pain, but also to maintain and modulate it. Dexmedetomidine (DEX), a highly selective agonist of α2-adrenergic receptor (α2-AR), has provided significant analgesia in neuropathic pain. In the present study, we found that local injection to sciatic nerve of DEX alleviated heat hypersensitivity induced by chronic constriction injury (CCI). Western blotting revealed that DEX inhibited the over-expression of nerve growth factor (NGF) significantly. Immunohistofluorescence results showed that DEX inhibited glia cells activation and sympathetic sprouting simultaneously in DRG. Our study suggests that DEX attenuates neuropathic pain in CCI rats by down-regulation of satellite glial cell (SGC) activation, NGF expression and sympathetic sprouting.
Fibromyalgia (FM) is a neuropathic pain syndrome that does not affect the joints, characterized by chronic diffuse musculoskeletal pain, being the most common cause of widespread pain of the general population. Investigations suggest that autonomic dysfunction, maintained by sympathetic activity, may explain the characteristics of FM that is a neuropathic pain syndrome. Dorsal root ganglia (DRG) are potential sites with sympathetic-nociceptive interaction. Sodium channels located in dorsal root ganglia, specifically the voltage-dependent sodium channels subtype 1.7 (Nav 1.7) act as a molecular gatekeepers controllers of the peripheral nociceptors on the detection of the pain. Trauma or infection can induce neuroplasticity with an overexpression of sympathetic fibers and sodium channels in dorsal root ganglia, so that the nerve growth factor mediates these phenotypic changes enabling catecholamines and/or sympathetic impulses to activate nociceptors. It has been proposed that enhanced GRD excitability may play a role in fibromyalgia pain. Individuals with FM are those genetically determined sympathetic hyperactivity, or those with inherent channelopathies Nav. In view of the foregoing, we will elucidate in this review, that the participation of Nav 1.7 in the genesis of FM, and possible selective channel blockers for this subtype, as a future therapeutic option for this disease.
Many patients with chronic fatigue syndrome (CFS) have widespread pain which has a large role in patients' activity limitations. Central sensitization has been posited as an explanation of this pain in both Fibromyalgia (FM) and CFS. Repeated or sustained noxious stimulation can lead to central sensitization, which can cause the spinal cord to enter a "hyperexcitable" state. In this article, we will explore the relevance of the central sensitization theory for CFS, as well as link it to the kindling hypothesis that has been previously offered as one explanation for the etiology of CFS. The article also reviews the implications of this theory for both inflammatory markers and central nervous system involvement.
Clinicians are often challenged by patients presenting with a syndrome of chronic and diffuse full body pain with long standing fatigue and a cluster of related symptoms. Fibromyalgia has become the commonly accepted term for this syndrome. Diagnosis is established through recognized subjective symptoms, such as tender points and other indicators of chronic full body pain and fatigue. Suspected triggers have included bacterial and viral infections, toxins, allergens, and emotional and physical trauma. Unknown causes limit the prescription of effective treatments; however, neuropathic pain and fatigue have been identified as key components so dual reuptake inhibitors and anti-convulsants have shown some effectiveness for some patients. Based upon laboratory and clinical studies of the last decade, this article proposes a model for a subset of fibromyalgia patients who have prolonged immune activation with related oxidative and nitrogenous stress leading to multiple hormonal repression, disrupted collagen physiology, neuropathic pain and fatigue. This integrative model of fibromyalgia is based on chronic up-regulation of the immune system with subsequent hormonal, connective tissue and nervous system implications.
This review imparts an impressionistic tone to our current understanding of autonomic nervous system abnormalities in fibromyalgia. In the wake of symptoms present in patients with fibromyalgia (FM), autonomic dysfunction seems plausible in fibromyalgia. A popular notion is that of a relentless sympathetic hyperactivity and hyporeactivity based on heart rate variability (HRV) analyses and responses to various physiological stimuli. However, some exactly opposite findings suggesting normal/hypersympathetic reactivity in patients with fibromyalgia do exist. This heterogeneous picture along with multiple comorbidities accounts for the quantitative and qualitative differences in the degree of dysautonomia present in patients with FM. We contend that HRV changes in fibromyalgia may not actually represent increased cardiac sympathetic tone. Normal muscle sympathetic nerve activity (MSNA) and normal autonomic reactivity tests in patients with fibromyalgia suggest defective vascular end organ in fibromyalgia. Previously, we proposed a model linking deconditioning with physical inactivity resulting from widespread pain in patients with fibromyalgia. Deconditioning also modulates the autonomic nervous system (high sympathetic tone and a low parasympathetic tone). A high peripheral sympathetic tone causes regional ischaemia, which in turn results in widespread pain. Thus, vascular dysregulation and hypoperfusion in patients with FM give rise to ischaemic pain leading to physical inactivity. Microvascular abnormalities are also found in patients with FM. Therapeutic interventions (e.g. exercise) that result in vasodilatation and favourable autonomic alterations have proven to be effective. In this review, we focus on the vascular end organ in patients with fibromyalgia in particular and its modulation by exercise in general.
The hypothesis of autonomic nervous system involvement in pathophysiology in the patients with fibromyalgia has been addressed and tested time and again but the existing reports are both contradictory and inconclusive. A complete knowledge of the degree of autonomic dysfunction in fibromyalgia patients would be more substantial. We conducted a comprehensive non-invasive study to investigate the complete autonomic profile of female patients with fibromyalgia.
An autonomic function test using a standard battery and heart rate variability analysis in the 42 fibromyalgia patients as well as 42 age matched healthy controls was performed. Both autonomic activity (tone) and reactivity were measured. Autonomic tone (both time and frequency domain parameters) was measured using heart rate variability (HRV) analysis. Autonomic reactivity was measured using a standard battery of autonomic function tests.
Resting blood pressure (both systolic and diastolic) was significantly higher in the fibromyalgia patients than controls. The time domain variables and HF% as recorded by HRV were significantly lower in the patients than the controls. The autonomic reactivity for sympathetic and parasympathetic nervous system was found to be within normal limits.
The cardiac autonomic function is normal and the autonomic reflex arc seems to be intact in the patients with fibromyalgia.
Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) is one of the more complex illnesses involving multiple systems within the body. Onset of ME/CFS frequently occurs quickly, and many patients report a prior exposure to a viral infection. This debilitating illness can affect the immune, neuroendocrine, autonomic, and neurologic systems. Abnormal biological findings among some patients have included aberrant ion transport and ion channel activity, cortisol deficiency, sympathetic nervous system hyperactivity, EEG spike waves, left ventricular dysfunction in the heart, low natural killer cell cytotoxicity, and a shift from Th1 to Th2 cytokines. We propose that the kindling and oxidative stress theories provide a heuristic template for better understanding the at times conflicting findings regarding the etiology and pathophysiology of this illness.
Duloxetine is a mixed serotonin-norepinephrine reuptake inhibitor used for major depressive disorder. Duloxetine is also beneficial for patients with diabetic peripheral neuropathy and with fibromyalgia, but how it works remains unclear.
We used the whole cell, patch clamp technique to test whether duloxetine interacts with the neuronal Nav1.7 Na+ channel as a potential target. Resting and inactivated Nav1.7 Na+ channel block by duloxetine were measured by conventional pulse protocols in transfected human embryonic kidney cells. The open-channel block was determined directly using inactivation-deficient mutant Nav1.7 Na+ channels.
The 50% inhibitory concentration (IC50) of duloxetine for the resting and inactivated wild-type hNav1.7 Na+ channel were 22.1+/-0.4 and 1.79+/-0.10 microM, respectively (mean+/-SE, n=5). The IC50 for the open Na+ channel was 0.25+/-0.02 microM (n=5), as determined by the block of persistent late Nav1.7 Na+ currents. Similar open-channel block by duloxetine was found in the muscle Nav1.4 isoform (IC50=0.51+/-0.05 microM; n=5). Block by duloxetine appeared via the conserved local anesthetic receptor as determined by site-directed mutagenesis. Finally, duloxetine elicited strong use-dependent block of neuronal transient Nav1.7 Na+ currents during repetitive stimulations.
Duloxetine blocks persistent late Nav1.7 Na+ currents preferentially, which may in part account for its analgesic action.
Although chronic pain states are highly prevalent, the underlying neurobiological mechanisms involved in causing pain are incompletely understood. This is especially true for the so-called chronic functional pain syndromes and pain syndromes of unknown origin, such as fibromyalgia (FM), in which no structural correlates of pain experience, in terms of a nociceptive source, can clearly be defined. In addition to limited therapeutic options and often unsatisfactory treatment, such patients often struggle with socio-medical acceptance of their pain condition. As FM has become more widely recognized, options available for treatment have grown along with our understanding of the neurobiological mechanisms underlying chronic pain experience and concomitant symptoms. The current review aims to provide an overview of existing pharmacotherapies for FM, and their implication for the underlying pathophysiology. Further we discuss some of the potential targets that have been recently identified that may hold promise for the development of novel treatments.
The nervous system modulates the immune response in many autoimmune syndromes by neurogenic inflammation. One of the pivotal mediators is nerve growth factor (NGF), which is known for its effects on neuronal survival and growth. There is considerable evidence that NGF acts as an important mediator of many immune responses. This article reviews the role of NGF in rheumatic diseases and strategies for potential therapeutic interventions.
We conducted a database search using Medline and Medpilot. Eight hundred abstracts containing the keyword NGF and 1 of the following terms were reviewed: arthritis, neurogenic inflammation, rheumatoid arthritis, osteoarthritis, collagen arthritis, arteritis, psoriasis, psoriatic arthritis, Sjogren syndrome, systemic lupus erythematosus, gout, osteoporosis, lower back pain, lumbar disc herniation, nerve root compression, spondyloarthritis, spondylarthropathy, algoneurodystrophy, fibromyalgia, Kawasaki syndrome, polyarteritis nodosa, cytokine, vasculitis, pain, therapy, and antagonist. Articles were analyzed based on relevance and content. Most clinical trials and studies with human specimens were included. Studies with experimental animal models were selected if they contained relevant data.
NGF is overexpressed in many inflammatory and degenerative rheumatic diseases. Concentrations differ to some extent and sometimes even show contradictory results. NGF is found in serum, synovial fluid, and cerebrospinal fluid, and tissue specimens. NGF concentrations can be correlated with the extent of inflammation and/or clinical activity in many conditions. In rheumatoid arthritis, NGF levels are significantly higher as compared with osteoarthritis.
NGF is a significant mediator and modulator of inflammation. NGF sometimes shows detrimental and sometimes regenerative activity. These findings indicate potential therapeutic interventions using either NGF antagonists or recombinant NGF.
Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase (COMT) that we designated as low pain sensitivity (LPS), average pain sensitivity (APS) and high pain sensitivity (HPS). We show that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated (P=0.0004) with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes. Inhibition of COMT in the rat results in a profound increase in pain sensitivity. Thus, COMT activity substantially influences pain sensitivity, and the three major haplotypes determine COMT activity in humans that inversely correlates with pain sensitivity and the risk of developing TMD.
To investigate the effects of intravenous lignocaine infusions (IV lignocaine) in fibromyalgia.
Prospective study of the adverse effects of IV lignocaine in 106 patients with fibromyalgia; retrospective questionnaire study of the efficacy of IV lignocaine in 50 patients with fibromyalgia.
Prospective study: Two major (pulmonary oedema and supraventricular tachycardia) and 42 minor side-effects were reported. None had long-term sequelae. The commonest was hypotension (17 cases). Retrospective study: Pain and a range of psychosocial measures (on single 11-point scales) improved significantly after treatment. There was no effect of the treatment on work status. The average duration of pain relief after the 6-day course of treatment was 11.5 +/- 6.5 weeks.
Intravenous lignocaine appears to be both safe and of benefit in improving pain and quality of life for patients with fibromyalgia. This needs to be confirmed in prospective randomised controlled trials.
During the nineties it was described, as an original finding, the existence of afferent amyelinic nerve endings in animal dorsal root ganglia (DRG) caused by diverse experimental lesions. These works do not take into account the historical studies carried out by Ehrlich (1886), Ramón y Cajal (1890) and Dogiel (1885) among others. Ramón y Cajal (1899) confirmed the existence of these nerve endings naming them after their discoverer as "Dogiel's arborisations". Ramón y Cajal claims that these endings originate from fibres of sympathetic nature, something supported by later authors devoted to this topic. In any case, the same authors remarked already a possible relationship with pathological phenomena, nonetheless always referring to the frequent occasions in which the same images appeared in healthy animals. In this work we review the bibliography about the classically named "Terminal Dogiel's nests" which in modern literature have been referred to as sprouting of sympathetic axons in dorsal root ganglia likely related with sympathetically maintained pain. Furthermore, we present the finding, not described up to date, of multiple afferent amyelinic nervous endings related with the "Terminal Dogiel's nests" observed in different DRG from young adult healthy rabbits.
This meta-analysis compares the prevalence of fatigue, musculoskeletal pain, and neurocognitive difficulties in patients who have had Lyme borreliosis (LB) and control subjects without LB.
Titles and abstracts in PubMed were reviewed for studies with data on the symptoms listed above that compared patients who had had LB with controls from the general population. Five studies with 504 patients and 530 controls were included in the meta-analysis.
The prevalence of symptoms was significantly higher in the LB patients, with P-values between <0.00001 and 0.007 for 8 of the 10 symptoms in the three categories listed above. The higher prevalence of certain neurocognitive symptoms but not others, in the same pattern as reported in the literature, is further confirmation of this syndrome. The pattern of symptoms appears to be different from that seen in fibromyalgia, depression, and chronic fatigue syndrome.
This meta-analysis provides strong evidence that some patients with LB have fatigue, musculoskeletal pain, and neurocognitive difficulties that may last for years despite antibiotic treatment.
Next Section
We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4–21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8–10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse “movies” reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism.
Autonomic dysfunction is frequent in patients with fibromyalgia (FM). Heart rate variability analyses have demonstrated signs of ongoing sympathetic hyperactivity. Catecholamines are sympathetic neurotransmitters. Catechol-O-methyltransferase (COMT), an enzyme, is the major catecholamine-clearing pathway. There are several single-nucleotide polymorphisms (SNPs) in the COMT gene associated with the different catecholamine-clearing abilities of the COMT enzyme. These SNPs are in linkage disequilibrium and segregate as 'haplotypes'. Healthy females with a particular COMT gene haplotype (ACCG) producing a defective enzyme are more sensitive to painful stimuli. The objective of our study was to define whether women with FM, from two different countries (Mexico and Spain), have the COMT gene haplotypes that have been previously associated with greater sensitivity to pain. All the individuals in the study were female. Fifty-seven Mexican patients and 78 Spanish patients were compared with their respective healthy control groups. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Six COMT SNPs (rs2097903, rs6269, rs4633, rs4818, rs4680, and rs165599) were genotyped from peripheral blood DNA. In Spanish patients, there was a significant association between three SNPs (rs6269, rs4818, and rs4680) and the presence of FM when compared with healthy controls. Moreover, in Spanish patients with the 'high pain sensitivity' haplotype (ACCG), the disease, as assessed by the FIQ, was more severe. By contrast, Mexican patients displayed only a weak association between rs6269 and rs165599, and some FIQ subscales. In our group of Spanish patients, there was an association between FM and the COMT haplotype previously associated with high pain sensitivity. This association was not observed in Mexican patients. Studies with a larger sample size are needed in order to verify or amend these preliminary results.
Objective:
To determine the prevalence of sexual and physical abuse in female patients with fibromyalgia syndrome (FMS), as compared with rheumatic disease control patients.
Methods:
Eighty-three female FMS patients and 161 consecutive female rheumatology (non-FMS) control patients answered a standardized confidential questionnaire recording previous sexual and physical abuse, drug and alcohol abuse, and eating disorders. Demographic information was collected on age, education, economic status, and cultural group.
Results:
Overall abuse was greater in FMS patients than in control patients (53% versus 42%; P not significant). Significant differences were observed for lifetime sexual abuse (17% versus 6%), physical abuse (18% versus 4%), combined physical and sexual abuse (17% versus 5%), and drug abuse (16% versus 3%). There was a trend toward a higher incidence of childhood sexual abuse (37% versus 22%) and of eating disorders (10% versus 3%) in the FMS patient group.
Conclusion:
A high frequency of sexual abuse was identified both in control patients and in FMS patients. A statistical association was demonstrated between FMS and the frequency and severity of sexual abuse, and the frequency of physical abuse and drug abuse. These results raise the possibility that abuse may have an effect upon the expression and perpetuation of FMS in adult life.
To study the relationship between cervical spine injury and the development of fibromyalgia syndrome (FMS).
One hundred two patients with neck injury and 59 patients with leg fractures (control group) were assessed for nonarticular tenderness and the presence of FMS. A count of 18 tender points was conducted by thumb palpation; and tenderness thresholds were assessed by dolorimetry at 9 tender sites. All patients were interviewed about the presence and severity of neck and FMS-related symptoms. FMS was diagnosed using the American College of Rheumatology 1990 criteria. Additional questions assessed measures of physical functioning and quality of life (QOL).
Although no patient had a chronic pain syndrome prior to the trauma, FMS was diagnosed following injury in 21.6% of those with neck injury versus 1.7% of the control patients with lower extremity fractures (P = 0.001). Almost all symptoms were more common and severe in the group with neck injury. FMS was noted at a mean of 3.2 months (SD 1.1) after the trauma. Neck injury patients with FMS (n = 22) had more tenderness, had more severe and prevalent FMS-related symptoms, and reported lower QOL and more impaired physical functioning than did those without FMS (n = 80). In spite of the injury or the presence of FMS, all patients were employed at the time of examination. Twenty percent of patients with neck injury and 24% of patients with leg fractures filed an insurance claim. Claims were not associated with the presence of FMS, increased FMS symptoms, pain, or impaired functioning.
FMS was 13 times more frequent following neck injury than following lower extremity injury. All patients continued to be employed, and insurance claims were not increased in patients with FMS.
A predominantly sensory peripheral neuropathy is common with human immunodeficiency virus (HIV) infection, but the cause is unknown. Formalin-fixed dorsal root ganglia (DRG), obtained at postmortem from patients with neuropathy and HIV infection and from control subjects, were examined for the presence of HIV DNA by using polymerase chain reaction (PCR)-amplified in situ hybridization. Viral message RNA was detected using reverse transcription in situ PCR with gag-specific primers. HIV DNA and RNA sequences were detected in many satellite cells, mononuclear cells, and occasional neurons in 5 of 5 patients with HIV and neuropathy. HIV DNA was detected only in rare interstitial and satellite cells from 3 of 4 patients with HIV infection without neuropathy and was not detected in 6 patients without HIV infection. HIV infection of DRG neurons and supporting cells may contribute to the HIV-associated sensory neuropathy.
To determine whether there is a difference in the concentration of nerve growth factor (NGF) in the cerebrospinal fluid (CSF) from patients diagnosed with primary fibromyalgia syndrome (FM), fibromyalgia associated with other secondary conditions (SFM), patients with other painful conditions but lacking fibromyalgia (OTHER), and healthy controls.
The clinical measures of pain threshold included the tender point index, a measure of pain threshold intensity measured by digital pressure, and the average pain threshold measured by dolorimetry. Concentrations of NGF in the CSF were measured using a 2 site enzyme immunoassay.
The mean (+/- SEM) concentration of NGF measured in patients with FM was significantly increased (41.8 +/- 12.7 pg/ml) compared to controls (9.1 +/- 4.1 pg/ml), but with large variability. Concentrations of NGF is SFM (8.9 +/- 4.4 pg/ml) and OTHER (16.2 +/- 8.4 pg/ml) were not elevated compared to controls.
The findings of increased concentrations of NGF in patients with FM suggest a central mechanism, involving abnormalities in neuropeptides such as NGF, may be a factor in the pathogenesis of FM.
The results of previous clinical trials have indicated that intraventricular infusion of nerve growth factor (NGF) in patients with Alzheimer's disease is frustrated by the appearance of weight loss and diffuse back pain. The present study tested whether NGF induces sympathetic sprouting in sensory ganglia. Such sprouting has been implicated in previous studies as a possible mechanism of sympathetically maintained pain in neuropathic animals.
Nineteen Long-Evans rats underwent intraventricular infusion of either artificial cerebrospinal fluid (ACSF; seven animals) or NGF (12 animals). After 14 days of infusion, the sensory ganglia of the trigeminal nerve and the C-2, C-8, T-1, L-4, and L-5 dorsal roots were examined for sympathetic sprouting by using tyrosine hydroxylase immunohistochemical analysis.
In the animals receiving NGF, 52 of 144 ganglia showed sympathetic fiber sprouting. In the control animals receiving ACSF, only two of 72 ganglia showed minor sympathetic fiber sprouting. A preferential sprouting of sympathetic fibers was demonstrated at lower lumbar ganglia compared with the cervical and thoracic ganglia. The data presented here demonstrate that in the rat intraventricular NGF infusion caused sympathetic sprouting in dorsal root ganglia (p < 0.01). These findings may have importance both for the treatment of Alzheimer's disease and the understanding of neuropathic pain.
Lyme borreliosis is caused by infection with the spirochete Borrelia burgdorferi. Nonhuman primates inoculated with the N40 strain of B. burgdorferi develop infection of multiple tissues, including the central (CNS) and peripheral nervous system. In immunocompetent nonhuman primates, spirochetes are present in low numbers in tissues. For this reason, it has been difficult to study their localization and changes in expression of surface proteins. To further investigate this, we inoculated four immunosuppressed adult Macaca mulatta with 1 million spirochetes of the N40 strain of B. burgdorferi, and compared them with three infected immunocompetent animals and two uninfected controls. The brain, spinal cord, peripheral nerves, skeletal muscle, heart, and bladder were obtained at necropsy 4 months later. The spirochetal tissue load was first studied by polymerase chain reaction (PCR)-ELISA of the outer surface protein A (ospA) gene. Immunohistochemistry was used to study the localization and numbers of spirochetes in tissues and the expression of spirochetal proteins and to characterize the inflammatory response. Hematoxylin and eosin and trichrome stains were used to study inflammation and tissue injury. The results showed that the number of spirochetes was significantly higher in immunosuppressed animals. B. burgdorferi in the CNS localized to the leptomeninges, nerve roots, and dorsal root ganglia, but not to the parenchyma. Outside of the CNS, B. burgdorferi localized to endoneurium and to connective tissues of peripheral nerves, skeletal muscle, heart, aorta, and bladder. Although ospA, ospB, ospC, and flagellin were present at the time of inoculation, only flagellin was expressed by spirochetes in tissues 4 months later. Significant inflammation occurred only in the heart, and only immunosuppressed animals had cardiac fiber degeneration and necrosis. Plasma cells were abundant in inflammatory foci of steroid-treated animals. We concluded that B. burgdorferi has a tropism for the meninges in the CNS and for connective tissues elsewhere in the body.
To define the frequency and characteristics of human immunodeficiency virus (HIV)-associated rheumatic manifestations in patients receiving highly active antiretroviral therapy (HAART) referred to a rheumatology clinic.
A total of 75 patients with HIV infection receiving HAART were prospectively evaluated for the presence of rheumatic complaints. Diagnosis of HIV infection was performed by ELISA and confirmed by Western blot, and all HIV patients were classified according to the US Centers for Disease Control criteria.
Seventy-five individuals with HIV infection and musculoskeletal manifestations were evaluated: 65 (86%) men and 10 (14%) women. Mean age was 32 +/- 4.5 years (range 21-58). The group included 40 (53%) heterosexuals, 30 (40%) intravenous drugs users, 9 (12%) homosexuals, 3 (4%) who had received blood transfusion, and 2 (2.6%) with unknown risk factors. Septic manifestations were the most common complications seen in 31 (41%) out of 75, and included septic arthritis, cellulitis, osteomyelitis, diskitis, and pyomyositis. Fibromyalgia was present in 13 (17%), seronegative symmetric polyarthritis in 4, oligoarthritis in 4, psoriatic arthritis in 2, carpal tunnel syndrome in 2, and enthesitis in 2. Mutifocal bone non-Hodgkin's lymphoma was present in 7 (9.3%) and Kaposis's sarcoma of bone in 2 (2.6%) patients. Hypertrophic osteoarthropathy in 3 (4%) and aseptic bone necrosis of multiple bones was seen in 3 (4%) patients. Ten patients exhibited only arthralgias. Most patients had moderately elevated erythrocyte sedimentation rate and C-reactive protein. Mean CD4 cell count was 250 mm3 (range 20-450), and mean HIV viral load was 5210 (range 0-75,300) copies/ml.
Rheumatic manifestations were highly frequent in HIV patients receiving HAART referred to a rheumatology clinic, although the clinical spectrum differed from the pre-HAART era with septic and malignant complications being the most common manifestations seen.
Abnormal activity of the sympathetic nervous system may be involved in the pathogenesis of chronic pain syndromes. This article reviews the animal studies of sympathetically induced pain behavior, the controversy of sympathetically maintained pain in clinical practice, and the dysautonomic nature of fibromyalgia (FM). FM has neuropathic pain features (stimuli-independent pain state accompanied by allodynia and paresthesias). The proposal of FM as a sympathetically maintained pain syndrome is based on the controlled studies showing that patients with FM display signs of relentless sympathetic hyperactivity and that the pain is submissive to sympathetic blockade and is rekindled by norepinephrine injections. Dysautonomia also may explain the multisystem features of FM.
Reactivation of latent varicella zoster virus (VZV) within sensory trigeminal and dorsal root ganglia (DRG) neurons produces shingles (zoster), often accompanied by a chronic neuropathic pain state, post-herpetic neuralgia (PHN). PHN persists despite latency of the virus within human sensory ganglia and is often unresponsive to current analgesic or antiviral agents. To study the basis of varicella zoster-induced pain, we have utilised a recently developed model of chronic VZV infection in rodents. Immunohistochemical analysis of DRG following VZV infection showed the presence of a viral immediate early gene protein (IE62) co-expressed with markers of A- (neurofilament-200; NF-200) and C- (peripherin) afferent sensory neurons. There was increased expression of neuropeptide Y (NPY) in neurons co-expressing NF-200. In addition, there was an increased expression of alpha2delta1 calcium channel, Na(v)1.3 and Na(v)1.8 sodium channels, the neuropeptide galanin and the nerve injury marker, Activating Transcription Factor-3 (ATF-3) as determined by Western blotting in DRG of VZV-infected rats. VZV infection induced increased behavioral reflex responsiveness to both noxious thermal and mechanical stimuli ipsilateral to injection (lasting up to 10 weeks post-infection) that is mediated by spinal NMDA receptors. These changes were reversed by systemic administration of gabapentin or the sodium channel blockers, mexiletine and lamotrigine, but not by the non-steroidal anti-inflammatory agent, diclofenac. This is the first time that the profile of VZV infection-induced phenotypic changes in DRG has been shown in rodents and reveals that this profile appears to be broadly similar (but not identical) to changes in other neuropathic pain models.
Cervical radicular pain affects 83 per 100,000 adults annually. Diagnosis by means of physical examination, imaging, and electrophysiological studies is characterized by high specificity but low sensitivity. In this review, we focus on the role of the dorsal root ganglion and those treatment modalities that aim at pathophysiological mechanisms occurring after injury to the dorsal root ganglion. Cervical nerve injury initiates multiple events that lead to changes in nerve function and result in spontaneous firing at the dorsal root ganglion. Among these, inflammation and changes in ion-channel function play a pivotal role. Although many treatment modalities are described in the literature, the available evidence for efficacy does not allow us to formulate definitive conclusions on the optimal therapy. A lack of evidence is reported for cervical spine surgery. Interlaminar epidural steroid administration and radiofrequency techniques adjacent to the cervical dorsal root ganglion have the highest, but still weak recommendations.
The dorsal root ganglion (DRG) of the spinal nerve has been considered a key structure in the mechanism of low-back pain and radicular symptoms. The purpose of this study was to clarify the normal morphologic features and variations of the lumbar DRGs in a healthy population by using 3D MR imaging.
3D fast-field echo (FFE) with water selective excitation coronal MR images of lumbar spine obtained in 115 healthy volunteers were further reconstructed into a radial stack of 15 coronal images by using maximum intensity projection technique. The DRGs from L1 through L5 were assessed for the location, signal intensity, architecture, and dimensions.
Most DGRs were foraminal in location. Only 5.7% of the L5 DGRs were located intraspinally. The sizes of L1, L2, and L5 DRGs in men were larger than those in women (P < .05). The dimensions of the DRGs gradually increased from L1 to L5 (P < .0001). The biganglia (2 ganglial components) frequently occurred in the L4 and L3 DRGs, whereas the singular ganglion (1 ganglial component), in the L5 and L1 DRGs.
The normal anatomy and variants of the lumbar DRG could be better demonstrated by 3D MR imaging with water selective excitation technique. The relatively larger and more proximally located DRGs in the lower lumbar region may be more susceptible to compression. An appreciation of normal anatomy and variants of DRGs radiologically is helpful for the diagnosis and proper treatment for radiculopathy.
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.
To investigate the regulatory effects of nerve growth factor (NGF) on basal and capsaicin-induced release of neuropeptide substance P (SP) in primary cultured embryonic rat dorsal root ganglion (DRG) neurons.
DRGs were dissected from 15-day-old embryonic Wistar rats. DRG neurons were dissociated and cultured, and then exposed to different concentrations of NGF (10 ng/mL, 30 ng/mL, or 100 ng/mL) for 72 h. The neurons cultured in media without NGF served as control. RT-PCR were used for detecting the mRNAs of SP and vanilloid receptor 1 (VR1) in the DRG neurons. The SP basal and capsaicin (100 nmol/L)-induced release in the culture were measured by radioimmunoassay (RIA).
SP mRNA and VR1 mRNA expression increased in primary cultured DRG neurons in a dose-dependent manner of NGF. Both basal release and capsaicin-evoked release of SP increased in NGF-treated DRG neurons compared with in control group. The capsaicin-evoked release of SP also increased in a dose-dependent manner of NGF.
NGF may promote both basal release and capsaicin-evoked release of SP. NGF might increase the sensitivity of nociceptors by increasing the SP mRNA or VR1 mRNA.
Voltage-dependent Na+ channels consist of the principal alpha-subunit (approximately 260 kDa), without or with auxiliary beta-subunit (approximately 38 kDa). Nine alpha-subunit isoforms (Na(v)1.1-Na(v)1.9) are encoded in nine different genes (SCN1A-SCN5A and SCN8A-SCN11A). Besides initiating and propagating action potentials in established neuronal circuit, Na+ channels engrave, maintain and repair neuronal network in the brain throughout the life. Adrenal chromaffin cells express Na(v)1.7 encoded in SCN9A, which is widely distributed among peripheral autonomic and sensory ganglia, neuroendocrine cells, as well as prostate cancer cell lines. In chromaffin cells, Na(v)1.7-specific biophysical properties have been characterized; physiological stimulation by acetylcholine produces muscarinic receptor-mediated hyperpolarization followed by nicotinic receptor-mediated depolarization. In human patients with Na(v)1.7 channelopathies, gain-of-pathological function mutants (i.e. erythermalgia and paroxysmal extreme pain disorder) or loss-of-physiological function mutant (channelopathy-associated insensitivity to pain) proved the causal involvement of mutant Na(v)1.7 in generating intolerable pain syndrome, Na(v)1.7 being the first molecular target convincingly identified for pain treatment. Importantly, aberrant upregulation/hyperactivity of even the native Na(v)1.7 produces pain associated with inflammation, nerve injury and diabetic neuropathy in rodents. Various extra- and intracellular signals, as well as therapeutic drugs modulate the activity of Na(v)1.7, and also cause up- and downregulation of Na(v)1.7. Na(v)1.7 seems to play an increasing number of crucial roles in health, disease and therapeutics.
The voltage-gated sodium-channel type IX alpha subunit, known as Na(v)1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential production in these cells. Recent genetic studies have identified Na(v)1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Na(v)1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Na(v)1.7 result in loss of Na(v)1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Na(v)1.7 in pain sensation in humans.
Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral nervous system, is a condition that severely affects the quality-of-life of millions of individuals worldwide. The treatment of neuropathic pain is still an unmet medical need; however, recent advances in our understanding of mechanisms underlying the perception and transmission of painful stimuli offer significant potential for improvement of therapies directed to neuropathic pain. Ectopic activity in damaged and dysfunctional sensory afferents is believed to have a role in the generation and maintenance of neuropathic pain. One of the mechanisms underlying this ectopic firing involves abnormal modulation of voltage-gated sodium channels (NaVs) in the soma and axonal membranes of dorsal root ganglion (DRG) sensory neurons. In fact, NaV blockers have been clinically validated as treatments for neuropathic pain. However, current drugs are weak, non-selective inhibitors of NaVs with dose-limiting CNS and cardiovascular side effects that prevent their use in long-term therapy. Selective NaV tetrodotoxin-resistant channels (NaV 1.8 and NaV 1.9) are expressed exclusively in nociceptive neurons in the DRGs where they play a key role in normal and/or pathological pain sensation, providing an opportunity for the development of novel peripheral analgesics with a better safety profile.
The Nav1.7 sodium channel plays an important role in pain and is also upregulated in prostate cancer. To investigate the mechanisms regulating physiological and pathophysiological Nav1.7 expression we identified the core promoter of this gene (SCN9A) in the human genome. In silico genomic analysis revealed a putative SCN9A 5' non-coding exon approximately 64,000 nucleotides from the translation start site, expression of which commenced at three very closely-positioned transcription initiation sites (TISs), as determined by 5' RACE experiments. The genomic region around these TISs possesses numerous core elements of a TATA-less promoter within a well-defined CpG island. Importantly, it acted as a promoter when inserted upstream of luciferase in a fusion construct. Moreover, the activity of the promoter-luciferase construct ostensibly paralleled endogenous Nav1.7 mRNA levels in vitro, with both increased in a quantitatively and qualitatively similar manner by numerous factors (including NGF, phorbol esters, retinoic acid, and Brn-3a transcription factor over-expression).
Identification and characterization of the promoter region of the Nav1.7 voltage-gated sodium channel gene (SCN9A)
- J K Diss
- M Calissano
- D Gascoyne
- M B Djmgoz
- D S Latchman
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Intraventricular infusion of nerve growth factor as the cause of sympathetic fiber sprouting in sensory ganglia
- H J Nauta
- J C Wehman
- V E Koliastos
- M A Terrel
- K Chung
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