Review

Authors: Lisette R M Raasing, Oscar J M Vogels, Marcel Veltkamp...

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

Review

Authors: Francis McGlone, Johan Wessberg, Håkan Olausson...

The multimodal properties of the human somatosensory system continue to be unravelled. There is mounting evidence that one of these submodalities-touch-has another dimension, providing not only its well-recognized discriminative input to the brain, but also an affective input. It has long been recognized that touch plays an important role in many forms of social communication and a number of theories have been proposed to explain observations and beliefs about the "power of touch." Here, we propose that a class of low-threshold mechanosensitive C fibers that innervate the hairy skin represent the neurobiological substrate for the affective and rewarding properties of touch.

Topics: Afferent Pathways; Central Nervous System; Discrimination, Psychological; Emotions; Humans; Nerve Fibers, Unmyelinated; Neural Conduction; Psychophysics; Skin Physiological Phenomena; Touch

PubMed: 24853935
DOI: 10.1016/j.neuron.2014.05.001

Authors: Xin Luo, Ouyang Chen, Zilong Wang...

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

Review

Authors: S Pertoldi, P Di Benedetto

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

Comparative Study

Authors: Jasmine Ji, Qianru He, Xin Luo...

The incidence of chronic pain is especially high in women, but the underlying mechanisms remain poorly understood. Interleukin-23 (IL-23) is a pro-inflammatory cytokine and contributes to inflammatory diseases (e.g., arthritis and psoriasis) through dendritic/T cell signaling. Here we examined the IL-23 involvement in sexual dimorphism of pain, using an optogenetic approach in transgenic mice expressing channelrhodopsin-2 (ChR2) in TRPV1-positive nociceptive neurons. hybridization revealed that compared to males, females had a significantly larger portion of small-sized (100-200 μm) neurons in dorsal root ganglion (DRG). Blue light stimulation of a hindpaw of transgenic mice induced intensity-dependent spontaneous pain. At the highest intensity, females showed more intense spontaneous pain than males. Intraplantar injection of IL-23 (100 ng) induced mechanical allodynia in females only but had no effects on paw edema. Furthermore, intraplantar IL-23 only potentiated blue light-induced pain in females, and intrathecal injection of IL-23 also potentiated low-dose capsaicin (500 ng) induced spontaneous pain in females but not males. IL-23 expresses in DRG macrophages of both sexes. Intrathecal injection of IL-23 induced significantly greater p38 phosphorylation (p-p38), a marker of nociceptor activation, in DRGs of female mice than male mice. In THP-1 human macrophages estrogen and chemotherapy co-application increased IL-23 secretion, and furthermore, estrogen and IL-23 co-application, but not estrogen and IL-23 alone, significantly increased IL-17A release. These findings suggest a novel role of IL-23 in macrophage signaling and female-dominant pain, including C-fiber-mediated spontaneous pain. Our study has also provided new insight into cytokine-mediated macrophage-nociceptor interactions, in a sex-dependent manner.

Topics: Animals; Capsaicin; Channelrhodopsins; Disease Models, Animal; Female; Ganglia, Spinal; Humans; Interleukin-17; Interleukin-23; Light; Macrophages; Male; Mice, Inbred C57BL; Mice, Transgenic; Nerve Fibers, Unmyelinated; Nociceptors; Optogenetics; Pain; Pain Threshold; Sex Characteristics; THP-1 Cells; TRPV Cation Channels; p38 Mitogen-Activated Protein Kinases; Mice

PubMed: 34950149
DOI: 10.3389/fimmu.2021.787565

Authors: Joshua D Vardigan, Parul S Pall, Dillon S McDevitt...

Voltage-gated sodium (Na v ) channels present untapped therapeutic value for better and safer pain medications. The Na v 1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human, possibly because of challenges in developing a sufficiently selective drug-like molecule with necessary potency not only in human but also across preclinical species critical to the preclinical development path of drug discovery. In addition, the relevance of rodent pain assays to the human condition is under increasing scrutiny as a number of mechanisms (or at the very least molecules) that are active in rodents have not translated to humans, and direct impact on pain fibers has not been confirmed in vivo. In this report, we have leveraged numerous physiological end points in nonhuman primates to evaluate the analgesic and pharmacodynamic activity of a novel, potent, and selective Na v 1.8 inhibitor compound, MSD199. These pharmacodynamic biomarkers provide important confirmation of the in vivo impact of Na v 1.8 inhibition on peripheral pain fibers in primates and have high translational potential to the clinical setting. These findings may thus greatly improve success of translational drug discovery efforts toward better and safer pain medications, as well as the understanding of primate biology of Na v 1.8 inhibition broadly.

Topics: Animals; Macaca mulatta; Nerve Fibers, Unmyelinated; Analgesics; Male; Pain; Pain Measurement; NAV1.8 Voltage-Gated Sodium Channel; Analgesia; Voltage-Gated Sodium Channel Blockers

PubMed: 39382325
DOI: 10.1097/j.pain.0000000000003404

Authors: Jing Feng, Yonghui Zhao, Zili Xie...

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

Authors: Dawei Zhang, Josef Turecek, Seungwon Choi...

Many hairy mammals perform rapid oscillations of their body, called wet dog shakes, to remove water and irritants from their back hairy skin. The somatosensory mechanisms that underlie this behavior are unclear. We report that Piezo2-dependent mechanosensation mediates wet dog shakes evoked by water or oil droplets applied to back hairy skin of mice. Unmyelinated C-fiber low-threshold mechanoreceptors (C-LTMRs) were activated by oil droplets, and their optogenetic activation elicited wet dog shakes. Ablation of C-LTMRs attenuated this behavior. Moreover, C-LTMRs synaptically couple to spinoparabrachial neurons, and optogenetically inhibiting spinoparabrachial neuron synapses and excitatory neurons in the parabrachial nucleus impaired both oil droplet- and C-LTMR-evoked wet dog shakes. Thus, a C-LTMR-spinoparabrachial pathway promotes wet dog shakes for removal of water and mechanical irritants from back hairy skin.

Topics: Animals; Mice; Mechanoreceptors; Nerve Fibers, Unmyelinated; Optogenetics; Parabrachial Nucleus; Water; Skin; Synapses; Male; Behavior, Animal

PubMed: 39509513
DOI: 10.1126/science.adq8834

Authors: Hiroki Ota, Haruna Takebe, Kazue Mizumura...

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

Review

Authors: Rochelle Ackerley, Roger Holmes Watkins

The technique of microneurography-recording neural traffic from nerves in awake humans-has provided us with unrivaled insights into afferent and efferent processes in the peripheral nervous system for over 50 years. We review the use of microneurography to study single C-fiber afferents and provide an overview of the knowledge gained, with views to future investigations. C-fibers have slowly conducting, thin-diameter, unmyelinated axons and make up the majority of the fibers in peripheral nerves (~80%). With the use of microneurography in humans, C-fiber afferents have been differentiated into discrete subclasses that encode specific qualities of stimuli on the skin, and their functional roles have been investigated. Afferent somatosensory information provided by C-fibers underpins various positive and negative affective sensations from the periphery, including mechanical, thermal, and chemical pain (C-nociceptors), temperature (C-thermoreceptors), and positive affective aspects of touch (C-tactile afferents). Insights from microneurographic investigations have revealed the complexity of the C-fiber system, methods for delineating fundamental C-fiber populations in a translational manner, how C-fiber firing can be used to identify nerve deficits in pathological states, and how the responses from C-fibers may be modified to change sensory percepts, including decreasing pain. Understanding these processes may lead to future medical interventions to diagnose and treat C-fiber dysfunction. NEW & NOTEWORTHY The technique of microneurography allows us to directly investigate the functional roles of single C-fiber afferents in awake human beings. Here we outline and discuss the current field of C-fiber research on this heterogeneous population of afferents in healthy subjects, in pathological states, and from a translational perspective. We cover C-fibers encoding touch, temperature, and pain and provide perspectives on the future of C-fiber microneurography investigations in humans.

Topics: Humans; Magnetic Resonance Imaging; Mechanoreceptors; Nerve Fibers, Unmyelinated; Nociceptors; Thermoreceptors

PubMed: 30256737
DOI: 10.1152/jn.00109.2018