Cutaneous Nerve Fibers Research Articles

Pilot study: ETPS therapy effectiveness versus Oral splint

Introduction: The temporomandibular disorders (TMD) are a group of diseases involving the masticatory muscles, the temporomandibular joint (TMJ) and other structures of the stomatognathic system. According to Cimmino et al. [1], TMD associated with chronic orofacial painful condition are the most common in general population. They are the most prevalent musculoskeletal pain, and in-between them, myofascial pain is the most frequent one [2]. This myalgia is characterized by the presence of tight and hypersensitive nodes to muscle palpation - trigger points [3]. A non-invasive treatment option is the Electrical Therapy Points Stimulation (ETPS), which promotes the continual stimulation of cutaneous nerve fibers resulting in a relief of musculoskeletal, neuropathic and nociceptive pain. The aim of this study was to assess the effectiveness of ETPS in patients with pain to palpation of Masseter muscles with origin in Temporomandibular Disorder (TMD) and, concomitantly, compare the ETPS with the conventional therapy with oral occlusal splint. Materials and methods: Random selection of 40 patients between 20 and 63 years, of both sexes. Patients with severe bruxism, periodontal disease, tooth decay, partially or totally toothless without being rehabilitated, with rheumatoid arthritis, osteoarthritis, osteoporosis, patients undergoing drug therapy with painkillers, muscle relaxants and anti-inflammatory drugs within the previous 30 days and patients with pacemaker were excluded. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) was applied always by the same observer (Level II calibrated). The sample was divided into 2 groups (n = 20), being: I-Treatment with ETPS and II- Treatment with Oral splint; Each patient was observed once a week in a total of three sessions. In each session, pain on palpation of masseter using a visual analogue scale (VAS) of 100 mm was performed. This observational study was approved by the Ethics Committee of University Institute Egas Moniz under reg. no. 54. Results: Table 1. Means and Standard Deviation for Masseteric pain to palpation using VAS. Student’s Paired t-Test found significant differences between both groups in sessions 2 and 3. *p ≤ 0.010 **p ≤ 0.05 Discussion and conclusions: To our knowledge, these results are new to the literature; This device showed more effectiveness than other types of physical therapy treatments [4,5]. However, time span of this study was short (3 weeks), viz. its results on long term are unknown. Both groups showed a reduction of pain palpation values, yet the ETPS group had always showed lower values, suggesting that in a short-term therapy with ETPS is more effective than the oral occlusal splint.

Transient receptor potential channels in the context of nociception and pain - recent insights into TRPM3 properties and function.

Potential harmful stimuli like heat, mechanical pressure or chemicals are detected by specialized cutaneous nerve fiber endings of nociceptor neurons in a process called nociception. Acute stimulation results in immediate protective reflexes and pain sensation as a normal, physiological behavior. However, ongoing (chronic) pain is a severe pathophysiological condition with diverse pathogeneses that is clinically challenging because of limited therapeutic options. Therefore, an urgent need exists for new potent and specific analgesics without afflicting adverse effects. Recently, TRPM3, a member of the superfamily of transient receptor potential (TRP) ion channels, has been shown to be expressed in nociceptors and to be involved in the detection of noxious heat (acute pain) as well as inflammatory hyperalgesia (acute and chronic pain). Current results in TRPM3 research indicate that this ion channel might not only be part of yet unraveled mechanisms underlying chronic pain but also has the potential to become a clinically relevant pharmacological target of future analgesic strategies. The aim of this review is to summarize and present the basic features of TRPM3 proteins and channels, to highlight recent findings and developments and to provide an outlook on emerging directions of TRPM3 research in the field of chronic pain.

The aggregation state of α-synuclein deposits in dermal nerve fibers of patients with Parkinson's disease resembles that in the brain

IntroductionPhosphorylated α-synuclein (p-α-syn) can be detected in dermal nerve fibers of patients with Parkinson's disease (PD) and multiple system atrophy (MSA). Here we investigated whether p-α-syn in the cutaneous nerve fibers represents misfolded aggregated protein. MethodsUsing immunofluorescence with conformation specific antibodies and digestion with proteinase K (PK), we studied skin biopsies from a cohort of patients with early stage PD (Hoehn and Yahr I/II, n=27), MSA with predominant parkinsonism (MSA-P, n=8) and normal controls (n=21). ResultsWe could show that α-synuclein (α-syn) found in the dermal nerve fibers in PD and MSA-P is not only phosphorylated but represents PK resistant and truncated aggregated protein. Comparison with a post mortem midbrain sample revealed a similar staining pattern of pathologic α-syn lesions in the PD brain. ConclusionImmunostaining of nerve fibers with different conformation specific antibodies and digestion with PK gave comparable results between midbrain and skin sections, showing that cutaneous nerve deposits of α-syn are structurally similar to Lewy pathology in the brain and are highly specific for synucleinopathy.

Muscle Fiber Type Changes in Lumbrical Muscles at Early Stages of Chronic Nerve Compression.

Chronic nerve compression (CNC) neuropathy is a common disease in the clinic and provokes paraesthesia, or numbness at early stage. The changes in muscle fiber composition and motor nerve terminal morphology in distal muscles were studied in this study. A well-established CNC model was used to assess the changes in the muscles. Behaviors were measured by von Frey filament test. The myosin heavy chain isoforms and neuromuscular junctions (NMJs) were stained by immunofluorescence to show the muscle fiber types composition and motor nerve terminals morphologic changes in the flexor digitorum longus (FDL) and lumbrical muscle. The fiber cross-sectional areas of different muscle fiber types were measured. The small-fiber degeneration of cutaneous nerve fibers was examined by detecting the protein gene product 9.5 (PGP9.5) with immunofluorescence. At 2nd month after compression, the proportion of type I and type II B fibers was markedly decreased, and that of type II A fibers was increased in the lumbrical muscle. There was no significant change in composition of muscle fiber types in FDL and NMJ morphology of FDL and lumbrical muscles. Intra-epidermal nerve fibre density (IENFD) declined at 2nd month after the compression. Our study reveals the morphological changes of the FDL and lumbrical muscle at an early stage of CNC. These findings may be helpful to understand muscle damage and pathophysiological development of the nerve compression, and provide new evidence for early treatment of CNC.

Tissue-Clearing Technique and Cutaneous Nerve Biopsies: Quantification of the Intraepidermal Nerve-Fiber Density Using Active Clarity Technique-Pressure Related Efficient and Stable Transfer of Macromolecules Into Organs.

Background and PurposeCutaneous nerve biopsies based on two-dimensional analysis have been regarded as a creditable assessment tool for diagnosing peripheral neuropathies. However, advancements in methodological imaging are required for the analysis of intact structures of peripheral nerve fibers. A tissue-clearing and labeling technique facilitates three-dimensional imaging of internal structures in unsectioned, whole biological tissues without excessive time or labor costs. We sought to establish whether a tissue-clearing and labeling technique could be used for the diagnostic evaluation of peripheral neuropathies.MethodsFive healthy individuals and four patients with small-fiber neuropathy (SFN) and postherpetic neuralgia (PHN) were prospectively enrolled. The conventional methods of indirect immunofluorescence (IF) and bright-field immunohistochemistry (IHC) were adopted in addition to the tissue-clearing and labeling method called active clarity technique-pressure related efficient and stable transfer of macromolecules into organs (ACT-PRESTO) to quantify the intraepidermal nerve-fiber density (IENFD).ResultsThe mean IENFD values obtained by IF, bright-field IHC, and ACT-PRESTO in the healthy control group were 6.54, 6.44, and 90.19 fibers/mm2, respectively; the corresponding values in the patients with SFN were 1.99, 2.32, and 48.12 fibers/mm2, respectively, and 3.06, 2.87, and 47.21 fibers/mm2, respectively, in the patients with PHN.ConclusionsThis study has shown that a tissue-clearing method provided not only rapid and highly reproducible three-dimensional images of cutaneous nerve fibers but also yielded reliable quantitative IENFD data. Quantification of the IENFD using a tissue-clearing and labeling technique is a promising way to improve conventional cutaneous nerve biopsies.

The Antipruritic Effect of Phototherapy.

Phototherapy is widely used to treat inflammatory skin diseases such as psoriasis and atopic dermatitis. Repeated suberythemogenic doses of UV-light reduce inflammation in these diseases and ultimately may lead to a complete disappearance of cutaneous symptoms for weeks or months. Chronic pruritus is an important and highly distressing symptom of many of these inflammatory skin diseases. Interestingly, pruritus is also reduced or completely abolished by UV-treatment of psoriasis and atopic dermatitis, and sometimes reduction of pruritus is the first indication for skin improvement by phototherapy. The cutaneous nervous system is an integral part of skin anatomy, and free nerve endings of sensory cutaneous nerve fibers reach up into the epidermis getting in close contact with epidermal cells and mediators from epidermal cells released into the intercellular space. Stimulation of “pruriceptors” within this group of sensory nerve fibers generates a neuronal signal eventually transmitted via the dorsal root and the spinal cord to the brain, where it is recognized as “itch”. UV-light may directly affect cutaneous sensory nerve fibers or, via the release of mediators from cells within the skin, indirectly modulate their function as well as the transmission of itch to the central nervous system inducing the clinically recognized antipruritic effect of phototherapy.

NOX, NOX, Are You Here? The Emerging Role of NOX5 in Diabetic Neuropathy

Diabetic neuropathy (DN) is one of the most common complications of diabetes worldwide, affecting up to 60% of all diabetic patients. Although the pathogenesis of DN is poorly understood, it is widely accepted that reactive oxygen species (ROS) mediate in part the cellular and molecular injury observed in DN. NADPH oxidase (Nox) enzymes generate ROS and of the 7 isoforms, NOX5 is present only in man. In this study, we aimed to investigate a role for NOX5 in DN by identifying the cellular localization, methylation status and expression levels of NOX5 in cutaneous nerve fibers and sural nerve biopsies of diabetic patients. Cellular localization of NOX5, myelin basic protein (MBP) and protein gene product (PGP) 9.5 were determined in cutaneous nerve fibers of controls and subjects with DN. NOX5 methylation status and protein levels were assessed in subjects with DN that were divided into two groups based on changes in sural nerve myelinated fiber density: regenerators (showing significant nerve regeneration) and degenerators (showing significant nerve degeneration). NOX5 expression was present in deep myelinated cutaneous fibers. Bisulfite sequencing revealed that the NOX5 promoter, enriched with CpG sites, is hypomethylated in sural nerve biopsies of the degenerator cohort compared to the regenerator. The increase in NOX5 expression in degenerator sural nerves was accompanied with a decrease in MBP levels relative to the regenerator group. Our results highlight that in subjects with DN with sural nerve degeneration, there is hypomethylation of the NOX5 promoter associated with an increase in its protein expression, suggesting a potential epigenetic and mechanistic role of NOX5 in DN. Disclosure S. Eid: None. J.M. Hayes: None. K. Guo: None. C. Pacut: None. F. Mendelson: None. J. Hur: None. E.L. Feldman: None.

Cutaneous somatic and autonomic nerve TDP-43 deposition in amyotrophic lateral sclerosis.

To evaluate the involvement of the sensory and autonomic nervous system in amyotrophic lateral sclerosis (ALS) and to determine whether TDP-43/pTDP-43 deposits in skin nerve fibers signify a valuable biomarker for ALS. Eighteen patients with ALS and 18 age- and sex-matched control subjects underwent physical examinations, in addition to donating skin biopsies from the distal leg. The density of epidermal, Meissner's corpuscle (MC), sudomotor, and pilomotor nerve fibers were measured. Confocal microscopy was used to determine the cutaneous somatic and autonomic nerve fiber density and TDP-43/pTDP-43 deposition. Intraepidermal nerve fiber density (IENFD) was reduced in individuals with ALS (P < 0.001). MC density (MCD) (P = 0.001), sweat gland nerve fiber density (SGNFD) (P < 0.001), and pilomotor nerve fiber density (PNFD) (P < 0.001) were all reduced in ALS patients. The SGNFD correlated with the small-fiber neuropathy Symptoms Inventory Questionnaire (SFN-SIQ), VAS and age. The SFN-SIQ was higher in ALS with sensory symptoms than without sensory symptoms (P = 0.000). Furthermore, the SFN-SIQ was higher in ALS with autonomic symptoms than without autonomic symptoms (P = 0.002). SFN-SIQ was higher in ALS patients that were pTDP-43 positive than pTDP-43 negative (P = 0.04), respectively. We established in the peripheral nervous system that higher SFN-SIQ and VAS was involved in ALS, indicating the loss of SGNF. The deposition of TDP-43/pTDP-43 in ALS nerve fibers may indicate an important role in the underlying pathogenesis of ALS. This observation might be used as a potential biomarker for diagnosing ALS.

A low dose of three local anesthetic solutions for interscalene blockade tested by thermal quantitative sensory testing: a randomized controlled trial.

This randomized double-blind controlled trial compared the block characteristics of three low-dose local anesthetics at different roots in an ultrasound-guided interscalene block, using thermal quantitative sensory testing for assessing the functioning of cutaneous small nerve fibres. A total of 37 adults scheduled to undergo shoulder arthroscopy were randomized to receive 5mL of either 0.5% levobupivacaine with and without epinephrine 1/200,000 or 0.75% ropivacaine in a single-shot interscalene block. Thermal quantitative sensory testing was performed in the C4, C5, C6 and C7 dermatomes. Detection thresholds for cold/warm sensation and cold/heat pain were measured before and at 30min, 6, 10 and 24h after infiltration around C5. The need for rescue medication was recorded. No significant differences between groups were found for any sensation (lowest P = 0.28). At 6h, the largest differences in sensory thresholds were observed for the C5 dermatome. The increase in thresholds were less in C4 and C6 and minimal in C7 for all sensations. The analgesic effect lasted the longest in C5 (time × location mixed model P < 0.001 for all sensory tests). The time to rescue analgesia was significantly shorter with 0.75% ropivacaine (P = 0.02). The quantitative sensory findings showed no difference in intensity between the local anesthetics tested. A decrease in block intensity, with minimal changes in pain detection thresholds, was observed in the roots adjacent to C5, with the lowest block intensity in C7. A clinically relevant shorter duration was found with 0.75% ropivacaine compared to the other groups. Trial registration NCT 02691442.

Juvenile murine models of prediabetes and type 2 diabetes develop neuropathy.

ABSTRACTPeripheral neuropathy (neuropathy) is a common complication of obesity and type 2 diabetes in children and adolescents. To model this complication in mice, 5-week-old male C57BL/6J mice were fed a high-fat diet to induce diet-induced obesity (DIO), a model of prediabetes, and a cohort of these animals was injected with low-dose streptozotocin (STZ) at 12 weeks of age to induce hyperglycemia and type 2 diabetes. Neuropathy assessments at 16, 24 and 36 weeks demonstrated that DIO and DIO-STZ mice displayed decreased motor and sensory nerve conduction velocities as early as 16 weeks, hypoalgesia by 24 weeks and cutaneous nerve fiber loss by 36 weeks, relative to control mice fed a standard diet. Interestingly, neuropathy severity was similar in DIO and DIO-STZ mice at all time points despite significantly higher fasting glucose levels in the DIO-STZ mice. These mouse models provide critical tools to better understand the underlying pathogenesis of prediabetic and diabetic neuropathy from youth to adulthood, and support the idea that hyperglycemia alone does not drive early neuropathy.This article has an associated First Person interview with the first author of the paper.

67. Cortical evoked potentials after stimulation of cutaneous nerve fibres by micro-patterned electrodes with different interrail gaps

To demonstrate that selective stimulation of intraepidermal nociceptive free endings can be performed using a micro-patterned comblike electrode with interrail gap of 150 μm. In 5 healthy subjects, we stimulated the skin of the hand dorsum with the micro-patterned electrode and with a similar electrode with interrail distance of 1 mm. Stimulation was performed with bursts of 10 pulses, 0.2 ms width each, period of 1 ms either delivered randomly or with constant rate. Cortical responses were recorded from Cz-Au and C3′/C4′-Fz. Stimulating with 1 mm electrode C3′/C4′ recordings showed N20 and W shaped SEP complex; Cz-Au derivation produced a smaller W complex and later smaller N1-P1 waves. Stimulating with 150 μm electrode C3′/C4′ recordings showed only the N1-P1 complex, while no early or medium-latency responses were visible; the Cz-Au recordings showed the N2-P2 complex. The 1 mm gap electrode stimulated large afferents, responsible of the medium-latency components of SEP W. Such components could not be detected with the 150 μm, indicating that large afferents were not stimulated and only small fibre nociceptive afferents were responsible for the late components. The micro-patterned electrode can be considered selective for nociceptive afferents.

Oral administration of milk-derived phospholipids inhibits penetration of cutaneous nerve fibres into epidermis in a mouse model of acute dry skin.

The density of intraepidermal nerve fibres has been shown to be higher in itchy dry skin than in healthy skin, suggesting that epidermal hyperinnervation is at least partly involved in peripheral itch sensitization. We investigated whether oral administration of milk-derived phospholipids (MPLs) would inhibit epidermal hyperinnervation in a mouse model of dry skin. We found that the number of intraepidermal nerve fibres was significantly lower in the MPL group than in the control group. Expression of nerve growth factor (NGF) levels in the epidermis was significantly decreased by oral administration of MPLs, whereas expression of semaphorin (Sema)3A, a nerve repulsion factor, was increased in the MPL group. These results suggest that dietary MPLs attenuate the penetration of nerve fibres into the epidermis by reducing epidermal NGF levels and increasing Sema3A level. Thus, dietary MPLs may have beneficial effects in the prevention and/or alleviation of dry skin-induced itch by reducing intraepidermal nerve fibre density.

Quantitative Thermal Testing Profiles as a Predictor of Treatment Response to Topical Capsaicin in Patients with Localized Neuropathic Pain.

There are no reliable predictors of response to treatment with capsaicin. Given that capsaicin application causes heat sensation, differences in quantitative thermal testing (QTT) profiles may predict treatment response. The aim of this study was to determine whether different QTT profiles could predict treatment outcomes in patients with localized peripheral neuropathic pain (PeLNP). We obtained from medical records QTT results and treatment outcomes of 55 patients treated between 2010 and 2013. Warm sensation threshold (WST) and heat pain threshold (HPT) values were assessed at baseline at the treatment site and in the asymptomatic, contralateral area. Responders were defined as those who achieved a > 30% decrease in pain lasting > 30 days. Two distinct groups were identified based on differences in QTT profiles. Most patients (27/31; 87.1%) with a homogenous profile were nonresponders. By contrast, more than half of the patients (13/24, 54.2%) with a nonhomogenous profile were responders (p = 0.0028). A nonhomogenous QTT profile appears to be predictive of response to capsaicin. We hypothesize patients with a partial loss of cutaneous nerve fibers or receptors are more likely to respond. By contrast, when severe nerve damage or normal cutaneous sensations are present, the pain is likely due to central sensitization and thus not responsive to capsaicin. Prospective studies with larger patient samples are needed to confirm this hypothesis.

Should Skin Biopsies Be Performed in Patients Suspected of Having Parkinson's Disease?

In patients with Parkinson's disease (PD), the molecularly misfolded form of α-synuclein was recently identified in cutaneous autonomic nerve fibers which displayed increased accumulation even in early disease stages. However, the underlying mechanisms of synucleinopathic nerve damage and its implication for brain pathology in later life remain to be elucidated. To date, specific diagnostic tools to evaluate small fiber pathology and to discriminate neurodegenerative proteinopathies are rare. Recently, research has indicated that deposition of α-synuclein in cutaneous nerve fibers quantified via immunohistochemistry in superficial skin biopsies might be a valid marker of PD which could facilitate early diagnosis and monitoring of disease progression. However, lack of standardization of techniques to quantify neural α-synuclein deposition limits their utility in clinical practice. Additional challenges include the identification of potential distinct morphological patterns of intraneural α-synuclein deposition among synucleinopathies to facilitate diagnostic discrimination and determining the degree to which structural damage relates to dysfunction of nerve fibers targeted by α-synuclein. Answering these questions might improve our understanding of the pathophysiological role of small fiber neuropathy in Parkinson's disease, help identify new treatment targets, and facilitate assessment of response to neuroprotective treatment.

Membrane properties in small cutaneous nerve fibers in humans

Assessment of membrane properties is important for understanding the mechanisms of painful peripheral neuropathy, developing new diagnostic techniques, and screening/profiling of analgesics that target ion channels. Small cutaneous nerves were activated electrically by small diameter (0.2 mm) cathodes, and large nerves were activated by ordinary patch electrodes. This new perception threshold tracking method combines perception threshold assessment and stimulation paradigms from conventional threshold tracking. The strength-duration time-constant of large fibers (580 µs ± 160 µs) was lower than the time constant of small fibers (1060 µs ± 690 µs; P < 0.01, paired t-test). Threshold electrotonus showed similar threshold reductions to sub-threshold prepulses, except for 80 ms hyperpolarizing prepulses, to which small fibers showed less threshold reduction than large fibers (repeated-measures analysis of variance, Bonferroni, P = 0.006). This is a reliable method to investigate the membrane properties of small cutaneous nerve fibers in humans and may be used in clinical settings as a diagnostic or profiling tool. Muscle Nerve 55: 195-201, 2017.

Alpha-synuclein in cutaneous small nerve fibers.

Despite progression in the development of pharmacological therapy, treatment of alpha synucleinopathies, such as Parkinson’s disease (PD) and some atypical parkinsonism syndromes, is still challenging. To date, our knowledge of the mechanisms whereby the pathological form of alpha-synuclein causes structural and functional damage to the nervous system is limited and, consequently, there is a lack of specific diagnostic tools to evaluate pathology in these patients and differentiate PD from other neurodegenerative proteinopathies. Recent studies indicated that alpha-synuclein deposition in cutaneous small nerve fibers assessed by skin biopsies might be a valid disease marker of PD and facilitate early differentiation of PD from atypical parkinsonism syndromes. This observation is relevant since early diagnosis may enable timely treatment and improve quality of life. However, challenges include the necessity of standardizing immunohistochemical analysis techniques and the identification of potential distinct patterns of intraneural alpha-synuclein deposition among synucleinopathies. In this perspective, we explore the scientific and clinical opportunities arising from alpha-synuclein assessment using skin biopsies. These include elucidation of the peripheral nervous system pathology of PD and other synucleinopathies, identification of novel targets to study response to neuroprotective treatment, and improvement of clinical management. Furthermore, we discuss future challenges in exploring the diagnostic value of skin biopsy assessment for alpha-synuclein deposition and implementing the technique in clinical practice.

The pruritus- and TH2-associated cytokine IL-31 promotes growth of sensory nerves

Pruritus is a cardinal symptom of atopic dermatitis, and an increased cutaneous sensory network is thought to contribute to pruritus. Although the immune cell-IL-31-neuron axis has been implicated in severe pruritus during atopic skin inflammation, IL-31's neuropoietic potential remains elusive. We sought to analyze the IL-31-related transcriptome in sensory neurons and to investigate whether IL-31 promotes sensory nerve fiber outgrowth. Invitro primary sensory neuron culture systems were subjected to whole-transcriptome sequencing, ingenuity pathway analysis, immunofluorescence, and nerve elongation, as well as branching assays after IL-31 stimulation. Invivo we investigated the cutaneous sensory neuronal network in wild-type, Il31-transgenic, and IL-31 pump-equipped mice. Transgenic Il31 overexpression and subcutaneously delivered IL-31 induced an increase in the cutaneous nerve fiber density in lesional skin invivo. Transcriptional profiling of IL-31-activated dorsal root ganglia neurons revealed enrichment for genes promoting nervous system development and neuronal outgrowth and negatively regulating cell death. Moreover, the growth cones of primary small-diameter dorsal root ganglia neurons showed abundant IL-31 receptor α expression. Indeed, IL-31 selectively promoted nerve fiber extension only in small-diameter neurons. Signal transducer and activator of transcription 3 phosphorylation mediated IL-31-induced neuronal outgrowth, and pharmacologic inhibition of signal transducer and activator of transcription 3 completely abolished this effect. In contrast, transient receptor potential cation channel vanilloid subtype 1 channels were dispensable for IL-31-induced neuronal sprouting. The pruritus- and TH2-associated novel cytokine IL-31 induces a distinct transcriptional program in sensory neurons, leading to nerve elongation and branching both invitro and invivo. This finding might help us understand the clinical observation that patients with atopic dermatitis experience increased sensitivity to minimal stimuli inducing sustained itch.

Pathophysiology of pruritus in primary localized cutaneous amyloidosis.

Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatosis prevalent among Southern Chinese and South American populations. Pruritus is frequently present and can be debilitating; its pathophysiology is largely unknown. To investigate if small-fibre neuropathy (SFN), which results in a reduction of intraepidermal nerve fibres (IENF) and abnormalities in quantitative thermal sensory testing (QST), is present in PLCA. Twenty Chinese patients (10 men) and 20 ethnicity-, sex- and age-matched controls underwent QST assessments. The patients' warm detection threshold (WDT) and heat pain threshold at the typical lesional sites were determined. Serum interleukin (IL)-31 levels were measured. Lesional biopsies were stained for IENF, IL-31 and its receptor's subunits [IL-31RA and oncostatin M receptor-β (OSMRβ)], and nerve growth factor (NGF) and its receptor [tropomyosin receptor kinase A (TrkA)], and were compared with normal skin obtained from archival paraffin-embedded specimens. WDT was significantly higher in patients at all sites and correlated with itch scores (r = 0·59; P < 0·01). Patient biopsies revealed lower IENF counts (P < 0·01 using protein gene product 9.5, β3-tubulin and Neurofilament 200 stains) and increased epidermal expression of OSMRβ (P < 0·01) and IL-31RA (P < 0·01). Cutaneous IL-31, NGF and TrkA stains were not significantly increased in patients. Serum IL-31 was not significantly higher in patients. SFN is present in PLCA. Pruritus in PLCA is likely associated with hypersensitivity of cutaneous nerve fibres, which may be related to an increased expression of epidermal IL-31 receptors. Targeting IL-31 receptors is therefore a potential therapeutic approach.

Sensitive skin.

Sensitive skin is a clinical condition defined by the self-reported facial presence of different sensory perceptions, including tightness, stinging, burning, tingling, pain and pruritus. Sensitive skin may occur in individuals with normal skin, with skin barrier disturbance, or as a part of the symptoms associated with facial dermatoses such as rosacea, atopic dermatitis and psoriasis. Although experimental studies are still pending, the symptoms of sensitive skin suggest the involvement of cutaneous nerve fibres and neuronal, as well as epidermal, thermochannels. Many individuals with sensitive skin report worsening symptoms due to environmental factors. It is thought that this might be attributed to the thermochannel TRPV1, as it typically responds to exogenous, endogenous, physical and chemical stimuli. Barrier disruptions and immune mechanisms may also be involved. This review summarizes current knowledge on the epidemiology, potential mechanisms, clinics and therapy of sensitive skin.

Transient Alterations of Cutaneous Sensory Nerve Function by Noninvasive Cryolipolysis

Cryolipolysis is a non-invasive, skin cooling treatment for local fat reduction that causes prolonged hypoesthesia over the treated area. We tested the hypothesis that cryolipolysis can attenuate nociception of a range of sensory stimuli, including stimuli that evoke itch. The effects of cryolipolysis on sensory phenomena were evaluated by quantitative sensory testing (QST) in 11 healthy subjects over a period of 56 days. Mechanical and thermal pain thresholds were measured on treated and contralateral untreated (control) flanks. Itch duration was evaluated following histamine iontophoresis. Unmyelinated epidermal nerve fiber and myelinated dermal nerve fiber densities were quantified in skin biopsies from six subjects. Cryolipolysis produced a marked decrease in mechanical and thermal pain sensitivity. Hyposensitivity started between two to seven days after cryolipolysis and persisted for at least thirty-five days post-treatment. Skin biopsies revealed that cryolipolysis decreased epidermal nerve fiber density as well as dermal myelinated nerve fiber density, which persisted throughout the study. In conclusion, cryolipolysis causes significant and prolonged decreases in cutaneous sensitivity. Our data suggest that controlled skin cooling to specifically target cutaneous nerve fibers has the potential to be useful for prolonged relief of cutaneous pain and might have a use as a research tool to isolate and study cutaneous itch-sensing nerves in human skin.