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Journal of Neuromuscular Diseases 2021Small fiber neuropathy (SFN) is a disorder of the small myelinated Aδ-fibers and unmyelinated C-fibers [5, 6]. SFN might affect small sensory fibers, autonomic fibers... (Review)
Review
Small fiber neuropathy (SFN) is a disorder of the small myelinated Aδ-fibers and unmyelinated C-fibers [5, 6]. SFN might affect small sensory fibers, autonomic fibers or both, resulting in sensory changes, autonomic dysfunction or combined symptoms [7]. As a consequence, the symptoms are potentially numerous and have a large impact on quality of life [8]. Since diagnostic methods for SFN are numerous and its pathophysiology complex, this extensive review focusses on categorizing all aspects of SFN as disease and its diagnosis. In this review, sensitivity in combination with specificity of different diagnostic methods are described using the areas under the curve. In the end, a diagnostic work-flow is suggested based on different phenotypes of SFN.
Topics: Autonomic Nervous System Diseases; Biopsy; Female; Humans; Male; Nerve Fibers, Unmyelinated; Quality of Life; Small Fiber Neuropathy
PubMed: 33337383
DOI: 10.3233/JND-200490 -
Neuron Sep 2021Although sex dimorphism is increasingly recognized as an important factor in pain, female-specific pain signaling is not well studied. Here we report that administration...
Although sex dimorphism is increasingly recognized as an important factor in pain, female-specific pain signaling is not well studied. Here we report that administration of IL-23 produces mechanical pain (mechanical allodynia) in female but not male mice, and chemotherapy-induced mechanical pain is selectively impaired in female mice lacking Il23 or Il23r. IL-23-induced pain is promoted by estrogen but suppressed by androgen, suggesting an involvement of sex hormones. IL-23 requires C-fiber nociceptors and TRPV1 to produce pain but does not directly activate nociceptor neurons. Notably, IL-23 requires IL-17A release from macrophages to evoke mechanical pain in females. Low-dose IL-17A directly activates nociceptors and induces mechanical pain only in females. Finally, deletion of estrogen receptor subunit α (ERα) in TRPV1 nociceptors abolishes IL-23- and IL-17-induced pain in females. These findings demonstrate that the IL-23/IL-17A/TRPV1 axis regulates female-specific mechanical pain via neuro-immune interactions. Our study also reveals sex dimorphism at both immune and neuronal levels.
Topics: Animals; Cells, Cultured; Estrogen Receptor alpha; Female; Humans; Interleukin-17; Interleukin-23; Macrophages; Male; Mice; Mice, Inbred C57BL; Nerve Fibers, Unmyelinated; Nociceptive Pain; Nociceptors; Sex Factors; Signal Transduction; TRPV Cation Channels
PubMed: 34473953
DOI: 10.1016/j.neuron.2021.06.015 -
Europa Medicophysica Dec 2005Complex regional pain syndrome (CRPS) types I and II are neuropathic pain disorders that develop as an exaggerated response to a traumatic lesion or nerve damage, that... (Review)
Review
Complex regional pain syndrome (CRPS) types I and II are neuropathic pain disorders that develop as an exaggerated response to a traumatic lesion or nerve damage, that generally affects the extremities, or as the consequence of a distant process such as a stroke, spinal lesion or myocardial infarction. It rarely appears without an apparent cause. CRPS of upper limbs after stroke is frequently today called shoulder-hand syndrome (SHS). The onset and severity of SHS appears to be related with the aetiology of the stroke, the severity and recovery of motor deficit, spasticity and sensory disturbances. Another important aetiological factor is glenohumeral subluxation. The physiopathology of the disease is still not known. In CRPS, there is an exaggerated inflammatory response and some chemical mediators have been identified and are present in the inflammatory soup around the primary afferent fibres that, through different processes, can induce hyper-excitability of the afferent fibres (peripheral sensitization). It is hypothesized that a localized neurogenic inflammation is at the basis of oedema, vasodilation and hyperhidrosis that are present in the initial phases of CRPS. The repeated discharge of the C fibres causes an increased medullary excitability (central sensitization). Another important factor is the reorganisation of the central nervous system, and in particular this appears to affect the primary somatosensory cortex. The central role of the sympathetic nerve is presently in doubt. However, it is thought that a sub-group of CRPS patients exists in whom a predominant factor is the hyper-activity of the sympathetic nervous system, and that it responds positively to sympathetic block. Diagnosis is clinical and there are no specific tests, nor pathognomic symptoms to identify this disease with certainty. Diagnosis of CRPS after stroke appears more complex than in other pathological situations: the paretic upper arm frequently appears painful, oedematose, with altered heat and tactile sensations and slightly dystrophic skin within a non-use syndrome. Some investigations can aid differential diagnosis with other diseases. Treatment may be non-pharmacological, pharmacological, with psychotherapy, regional anaesthesia, neuromodulation and sympathectomy. In any case there is little evidence that supports the efficacy of the interventions normally used to treat or prevent CRPS-SHS. The key to effective treatment undoubtedly lies in a an expert multidisciplinary team that is co-ordinated and motivated and that treats the disorder with individualised therapy.
Topics: Algorithms; Humans; Nerve Fibers, Unmyelinated; Reflex Sympathetic Dystrophy; Stroke; Sympathetic Nervous System
PubMed: 16474282
DOI: No ID Found -
Science Translational Medicine Jul 2022Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of...
Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3 pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle.
Topics: Humans; Merkel Cells; Nerve Fibers, Unmyelinated; Pruritus; Sensory Receptor Cells; Skin
PubMed: 35857641
DOI: 10.1126/scitranslmed.abn4819 -
Pulmonary Pharmacology & Therapeutics Jun 2019Activation of vagal C-fibers is likely involved in some types of pathological coughing, especially coughing that is associated with airway inflammation. This is because... (Review)
Review
Activation of vagal C-fibers is likely involved in some types of pathological coughing, especially coughing that is associated with airway inflammation. This is because stimulation of vagal C-fibers leads to strong urge to cough sensations, and because C-fiber terminals can be strongly activated by mediators associated with airway inflammation. The most direct manner in which a given mediator can activate a C-fiber terminal is through interacting with its receptor expressed in the terminal membrane. The agonist-receptor interaction then must lead to the opening (or potentially closing) of ion channels that lead to a membrane depolarization. This depolarization is referred to as a generator potential. If, and only if, the generator potential reaches the voltage necessary to activate voltage-gated sodium channels, action potentials are initiated and conducted to the central terminals within the CNS. Therefore, there are three target areas to block the inflammatory mediator induced activation of C-fiber terminals. First, at the level of the mediator-receptor interaction, secondly at the level of the generator potential, and third at the level of the voltage-gated sodium channels. Here we provide a brief overview of each of these therapeutic strategies.
Topics: Action Potentials; Animals; Antitussive Agents; Cough; Humans; Nerve Fibers, Unmyelinated; Vagus Nerve; Voltage-Gated Sodium Channels
PubMed: 30872160
DOI: 10.1016/j.pupt.2019.03.002 -
Neuroscience and Biobehavioral Reviews Aug 2023Since their initial discovery in cats, low-threshold C-fiber mechanoreceptors have become a central interest of scientists studying the affective aspects of touch. Their... (Review)
Review
Since their initial discovery in cats, low-threshold C-fiber mechanoreceptors have become a central interest of scientists studying the affective aspects of touch. Their pursuit in humans, here termed C-tactile (CT) afferents, has led to the establishment of a research field referred to as "affective touch", which is differentiated from "discriminative touch". Presently, we review these developments based on an automated semantic analysis of more than 1000 published abstracts as well as empirical evidence and the solicited opinions of leading experts in the field. Our review provides a historical perspective and update of CT research, it reflects on the meaning of "affective touch", and discusses how current insights challenge established views on the relation between CTs and affective touch. We conclude that CTs support gentle, affective touch, but that not every affective touch experience relies on CTs or must necessarily be pleasant. Moreover, we speculate that currently underappreciated aspects of CT signaling will prove relevant for the manner in which these unique fibers support how humans connect both physically and emotionally.
Topics: Humans; Animals; Cats; Touch; Touch Perception; Mechanoreceptors; Emotions; Nerve Fibers, Unmyelinated; Physical Stimulation
PubMed: 37196923
DOI: 10.1016/j.neubiorev.2023.105236 -
Microbiology Spectrum Dec 2022Stimulation of unmyelinated C fibers, the nociceptive sensory nerves, by noxious stimuli is able to initiate host responses. Host defensive responses against respiratory...
Stimulation of unmyelinated C fibers, the nociceptive sensory nerves, by noxious stimuli is able to initiate host responses. Host defensive responses against respiratory syncytial virus (RSV) infection rely on the induction of a robust alpha/beta interferon (IFN-α/β) response, which acts to restrict viral production and promote antiviral immune responses. Alveolar macrophages (AMs) are the major source of IFN-α/β upon RSV infection. Here, we found that C fibers are involved in host defense against RSV infection. Compared to the control mice post-RSV infection, degeneration and inhibition of C fibers by blockade of transient receptor potential vanilloid 1 (TRPV1) lowered viral replication and alleviated lung inflammation. Importantly, AMs were markedly elevated in C-fiber-degenerated (KCF) mice post-RSV infection, which was associated with higher IFN-α/β secretion as measured in bronchoalveolar lavage fluid (BALF) samples. Degeneration of C fibers contributed to the production of vasoactive intestinal peptide (VIP), which modulated AM and IFN-α/β levels to protect against RSV infection. Collectively, these findings revealed the key role of C fibers in regulating AM and IFN-α/β responses against RSV infection via VIP, opening the possibility for new therapeutic strategies against RSV. Despite continuous advances in medicine, safe and effective drugs against RSV infection remain elusive. As such, host-RSV interactions and host-directed therapies require further research. Unmyelinated C fibers, the nociceptive sensory nerves, play an important role in regulating the host response to virus. In the present study, from the perspective of neuroimmune interactions, we clarified that C-fiber degeneration enhanced the AM-mediated IFN-α/β response against RSV via VIP, providing potential therapeutic targets for the treatment of RSV infection.
Topics: Animals; Mice; Macrophages, Alveolar; Nerve Fibers, Unmyelinated; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Interferon-beta; Lung
PubMed: 36350149
DOI: 10.1128/spectrum.02410-22 -
Respiratory Physiology & Neurobiology Jul 2020Inflammation can increase the excitability of bronchopulmonary C-fibers leading to excessive sensations and reflexes (e.g. wheeze and cough). We have previously shown...
Inflammation can increase the excitability of bronchopulmonary C-fibers leading to excessive sensations and reflexes (e.g. wheeze and cough). We have previously shown modulation of peripheral nerve terminal mitochondria by antimycin A causes hyperexcitability in TRPV1-expressing bronchopulmonary C-fibers through the activation of protein kinase C (PKC). Here, we have investigated the PKC isoform responsible for this signaling. We found PKCβ1, PKCδ and PKCε were expressed by many vagal neurons, with PKCα and PKCβ2 expressed by subsets of vagal neurons. In dissociated vagal neurons, antimycin A caused translocation of PKCα but not the other isoforms, and only in TRPV1-lineage neurons. In bronchopulmonary C-fiber recordings, antimycin A increased the number of action potentials evoked by α,β-methylene ATP. Selective inhibition of PKCα, PKCβ1 and PKCβ2 with 50 nM bisindolylmaleimide I prevented the antimycin-induced bronchopulmonary C-fiber hyperexcitability, whereas selective inhibition of only PKCβ1 and PKCβ2 with 50 nM LY333531 had no effect. We therefore conclude that PKCα is required for antimycin-induced increases in bronchopulmonary C-fiber excitability.
Topics: Animals; Antimycin A; Bronchi; Lung; Mice; Nerve Fibers, Unmyelinated; Neurons; Nodose Ganglion; Protein Isoforms; Protein Kinase C; Protein Kinase C-alpha; TRPV Cation Channels; Vagus Nerve
PubMed: 32360368
DOI: 10.1016/j.resp.2020.103446 -
Physiology (Bethesda, Md.) Jan 2020Stimulation of bronchopulmonary vagal afferent C fibers by inflammatory mediators can lead to coughing, chest tightness, and changes in breathing pattern, as well as... (Review)
Review
Stimulation of bronchopulmonary vagal afferent C fibers by inflammatory mediators can lead to coughing, chest tightness, and changes in breathing pattern, as well as reflex bronchoconstriction and secretions. These responses serve a defensive function in healthy lungs but likely contribute to many of the signs and symptoms of inflammatory airway diseases. A better understanding of the mechanisms underlying the activation of bronchopulmonary C-fiber terminals may lead to novel therapeutics that would work in an additive or synergic manner with existing anti-inflammatory strategies.
Topics: Animals; Cough; Humans; Inflammation Mediators; Lung; Nerve Fibers, Unmyelinated; Reflex; Vagus Nerve
PubMed: 31799905
DOI: 10.1152/physiol.00014.2019 -
The Journal of Physiological Sciences :... Jun 2021Previous studies have shown that persistent limb immobilization using a cast increases nociceptive behavior to somatic stimuli in rats. However, the peripheral neural...
Previous studies have shown that persistent limb immobilization using a cast increases nociceptive behavior to somatic stimuli in rats. However, the peripheral neural mechanisms of nociception remain unclear. Using single-fiber electrophysiological recordings in vitro, we examined the general characteristics of cutaneous C-fiber afferents in the saphenous nerve and their responsiveness to mechanical and heat stimuli in a rat model of immobilization-induced pain by subjecting the rats to hindlimb cast immobilization for 4 weeks. The mechanical response of C-fibers appeared to increase in the model; however, statistical analysis revealed that neither the response threshold nor the response magnitude was altered. The general characteristics and heat responses of the C-fibers were not altered. The number of microglia and cell diameters significantly increased in the superficial dorsal horn of the lumbar spinal cord. Thus, activated microglia-mediated spinal mechanisms are associated with the induction of nociceptive hypersensitivity in rats after persistent cast immobilization.
Topics: Animals; Casts, Surgical; Hindlimb; Immobilization; Male; Microglia; Nerve Fibers, Unmyelinated; Neurons, Afferent; Nociception; Pain Measurement; Rats; Rats, Sprague-Dawley; Skin; Spinal Cord
PubMed: 34162322
DOI: 10.1186/s12576-021-00803-3