Dermal Nerve Research Articles

Charcot-Marie-Tooth disease: New insights from skin biopsy.

To evaluate, by skin biopsy, dermal nerve fibers in 31 patients with 3 common Charcot-Marie-Tooth (CMT) genotypes (CMT1A, late-onset CMT1B, and CMTX1), and rarer forms of CMT caused by mutations in RAB7 (CMT2B), TRPV4 (CMT2C), and GDAP1 (AR-CMT2K) genes. We investigated axonal loss by quantifying Meissner corpuscles and intrapapillary myelinated endings and evaluated morphometric changes in myelinated dermal nerve fibers by measuring fiber caliber, internodal, and nodal gap length. The density of both Meissner corpuscles and intrapapillary myelinated endings was reduced in skin samples from patients with CMT1A and all the other CMT genotypes. Nodal gaps were larger in all the CMT genotypes though widening was greater in CMT1A. Perhaps an altered communication between axons and glia may be a common feature for multiple forms of CMT. Internodal lengths were shorter in all the CMT genotypes, and patients with CMT1A had the shortest internodes of all our patients. The uniformly shortened internodes in all the CMT genotypes suggest that mutations in both myelin and axon genes may developmentally impede internode formation. The extent of internodal shortening and nodal gap widening are likely both important in determining nerve conduction velocities in CMT. This study extends the information gained from skin biopsies on morphologic abnormalities in various forms of CMT and provides insights into potential pathomechanisms of axonal and demyelinating CMT.

Peripheral synuclein tissue markers: a step closer to Parkinson's disease diagnosis.

This scientific commentary refers to ‘Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson’s disease from multiple system atrophy’, by Zange et al. (doi:10.1093/brain/awv138). Intraneuronal Lewy bodies and Lewy neurites consisting of aggregated α-synuclein (SNCA) are the hallmark of brain pathology in Parkinson’s disease. It is now well established that Lewy-type α-synuclein histopathology also occurs in the peripheral autonomic nervous system (Beach et al. , 2010; Gelpi, 2014), and recent efforts have been directed towards detection of this pathology in peripheral tissues in the hope that it could serve as diagnostic biomarker of Parkinson’s disease. Such a tissue marker would differentiate Parkinson’s disease from mimics and related conditions such as multiple system atrophy (MSA), essential tremor and vascular parkinsonism, which are not associated with Lewy-type α-synucleinopathy. In this issue of Brain , Zange et al. present the results of one such study on peripheral SNCA, and report the presence of phosphorylated α-synuclein (pSNCA) deposits in the dermal nerves of patients with Parkinson’s disease, but not MSA or essential tremor, consistent with what one might expect from the known pathology of these disorders (Zange et al. , 2015). The results thus suggest that a simple forearm skin biopsy could permit the separation of these conditions. Zange et al. also describe changes compatible with a neuropathy in their subjects with Parkinson’s disease. As they observed a correlation between the pSNCA deposits and denervation of autonomic skin elements that was independent of age or disease duration, they suggest, as others have previously (Donadio et al. , 2014), that pSNCA is causative for the nerve fibre degeneration. However, no conclusive evidence for this exists. The situation is similar to that in the CNS in Parkinson’s disease, where it is unclear if Lewy bodies and neurites are …

Boundary Caps Give Rise to Neurogenic Stem Cells and Terminal Glia in the Skin

SummaryWhile neurogenic stem cells have been identified in rodent and human skin, their manipulation and further characterization are hampered by a lack of specific markers. Here, we perform genetic tracing of the progeny of boundary cap (BC) cells, a neural-crest-derived cell population localized at peripheral nerve entry/exit points. We show that BC derivatives migrate along peripheral nerves to reach the skin, where they give rise to terminal glia associated with dermal nerve endings. Dermal BC derivatives also include cells that self-renew in sphere culture and have broad in vitro differentiation potential. Upon transplantation into adult mouse dorsal root ganglia, skin BC derivatives efficiently differentiate into various types of mature sensory neurons. Together, this work establishes the embryonic origin, pathway of migration, and in vivo neurogenic potential of a major component of skin stem-like cells. It provides genetic tools to study and manipulate this population of high interest for medical applications.

Distinctive distribution of phospho-alpha-synuclein in dermal nerves in multiple system atrophy.

MSA is characterized by deposition of alpha-synuclein (α-Syn) in oligodendrocytes and central nervous system (CNS) neurons. After recently detecting phospho-α-Syn (p-α-Syn) in dermal nerve fibers of patients with Parkinson's disease (PD), we assessed skin biopsies from patients with MSA to evaluate its potential role as a biomarker. Skin biopsies of patients with MSA (n = 12), idiopathic PD (n = 30), tauopathies (n = 15), and normal controls (n = 39) were analyzed. P-α-Syn within dermal nerves was detected by immunofluorescence staining. p-α-Syn was found in 67% of patients with MSA and Parkinson's disease, but not in patients with tauopathy or controls when analyzing 15 consecutive sections. Sensitivity could be increased to 75% and 73%, respectively, by analyzing serial sections. In contrast to PD, where p-α-Syn clustered in autonomic fibers, deposits were mainly found in unmyelinated somatosensory fibers in MSA. α-Syn pathology in MSA is not restricted to the CNS, and skin biopsy may be useful for the premortem study of p-α-Syn.

Absence of Dystrophin Related Protein-2 disrupts Cajal bands in a patient with Charcot–Marie–Tooth disease

Using exome sequencing in an individual with Charcot–Marie–Tooth disease (CMT) we have identified a mutation in the X-linked dystrophin-related protein 2 (DRP2) gene. A 60-year-old gentleman presented to our clinic and underwent clinical, electrophysiological and skin biopsy studies. The patient had clinical features of a length dependent sensorimotor neuropathy with an age of onset of 50 years. Neurophysiology revealed prolonged latencies with intermediate conduction velocities but no conduction block or temporal dispersion. A panel of 23 disease causing genes was sequenced and ultimately was uninformative. Whole exome sequencing revealed a stop mutation in DRP2, c.805C>T (Q269*). DRP2 interacts with periaxin and dystroglycan to form the periaxin–DRP2–dystroglycan complex which plays a role in the maintenance of the well-characterized Cajal bands of myelinating Schwann cells. Skin biopsies from our patient revealed a lack of DRP2 in myelinated dermal nerves by immunofluorescence. Furthermore electron microscopy failed to identify Cajal bands in the patient's dermal myelinated axons in keeping with ultrastructural pathology seen in the Drp2 knockout mouse. Both the electrophysiologic and dermal nerve twig pathology support the interpretation that this patient's DRP2 mutation causes characteristic morphological abnormalities recapitulating the Drp2 knockout model and potentially represents a novel genetic cause of CMT.

Characterization of small nerve fibers in painful distal symmetric polyneuropathy and healthy controls

Abstract Aims The introduction of skin biopsies to examine small nerve fiber morphology together with functional measures such as quantitative sensory testing (QST) has led to an improvement in diagnosing patients with small fiber neuropathy (SFN). Quantification of intraepidermal nerve fiber density (IENFD) is an important measure in SFN. However, the relationship between structure and function is not straightforward and the morphological and functional fiber characteristics are still unclear. This study aimed to combine structural and functional measurements to improve the diagnosis of distal symmetric polyneuropathy and small fiber involvement. Additionally, we investigated whether patients and healthy controls have differential patterns of correlations between structural and functional nerve measurements. Methods 17 patients with painful distal symmetric polyneu-ropathy (DSP) and 19 controls underwent comprehensive small fiber assessments that included quantitative sensory testing, response to topical capsaicin and analysis of skin biopsy samples (IENFD, epidermal and dermal nerve fiber length densities (eNFLD, dNFLD) and swellings). Results DSP patients had reduced sensitivity to cold and heat, diminished capsaicin response, and lower IENFD, eNFLD and dNFLD (all p < 0.0003).The correlation between structural and functional parameters was better in controls than in DSP. A diagnostic approach of combined IENFD and eNFLD utilization, increased DSP diagnostic sensitivity from 82.0% to 100% and specificity from 84.0% to 89.5%. Conclusions A correlation is found between functional and structural small fiber parameters for DSP and controls, and an approach to improve diagnostic accuracy in DSP is suggested.

Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson's disease from multiple system atrophy.

Deposition of phosphorylated SNCA (also known as α-synuclein) in cutaneous nerve fibres has been shown pre- and post-mortem in Parkinson's disease. Thus far, no pre-mortem studies investigating the presence of phosphorylated SNCA in skin sympathetic nerve fibres of multiple system atrophy, another synucleinopathy, have been conducted. In this in vivo study, skin from the ventral forearm of 10 patients with multiple system atrophy and 10 with Parkinson's disease, together with six control subjects with essential tremor, were examined by immunohistochemistry. Phosphorylated SNCA deposits in skin sympathetic nerve fibres and dermal nerve fibre density were assessed. All patients with Parkinson's disease expressed phosphorylated SNCA in sympathetic skin nerve fibres, correlating with an age-independent denervation of autonomic skin elements. In contrast, no phosphorylated SNCA was found in autonomic skin nerve fibres of patients with multiple system atrophy and essential tremor control subjects. These findings support that phosphorylated SNCA deposition is causative for nerve fibre degeneration in Parkinson's disease. Moreover, pre-mortem investigation of phosphorylated SNCA in cutaneous nerve fibres may prove a relevant and easily conductible diagnostic procedure to differentiate Parkinson's disease from multiple system atrophy.

Up-regulation of cutaneous α1-adrenoceptors after a burn

Stimulation of α1-adrenoceptors evokes inflammatory cytokine production, boosts neurogenic inflammation and pain, and influences cellular migration and proliferation. As expression of α1-adrenoceptors increases on dermal nerves and keratinocytes after peripheral nerve injury, the aim of this study was to determine whether another form of tissue injury (a cutaneous burn) triggered a similar response. In particular, changes in expression of α1-adrenoceptors were investigated on dermal nerve fibres, keratinocytes and fibroblast-like cells using immunohistochemistry 2–12 weeks after a full thickness burn in Wistar rats. Within two weeks of the burn, local increases in α1-adrenoceptor expression were seen in the re-forming epidermis, in dense bands of spindle-shaped cells in the upper dermis (putatively infiltrating immune cells and fibroblasts), and on nerve fibres in the deep dermis. In addition, nerve fibre density increased approximately three-fold in the deep dermis, and this response persisted for several more weeks. In contrast, α1-adrenoceptor labelled cells and staining intensity in the upper dermis decreased contralateral to the burn, as did nerve fibre density in the deep dermis. These findings suggest that inflammatory mediators and/or growth factors at the site of a burn trigger the synthesis of α1-adrenoceptors on resident epidermal cells and nerve fibres, and an influx of α1-adrenoceptor labelled cells. The heightened expression of α1-adrenoceptors in injured tissue could shape inflammatory and wound healing responses.

Immunohistochemical examination of skin biopsy specimens with calculation of C fibers in the diagnosis of polyneuropathy

The paper discusses the anatomy of innervation of the skin, the epidermis and dermis in particular, which are related to pain, the markers of skin nerves and cells. It gives data on the diagnosis of fine unmyelinated fibers, by immunohistochemically examining skin biopsy specimens. The paper also describes the morphometry of skin nerves: intraepidermal nerve fibers, dermal nerve fibers, and autonomic nerve fibers. It discusses whether a skin biopsy specimen may be used to diagnose polyneuropathies of different etiology: diabetic, immune, HIV-related, and hereditary ones.

Mechanisms of nerve injury in leprosy

All patients with leprosy have some degree of nerve involvement. Perineural inflammation is the histopathologic hallmark of leprosy, and this localization may reflect a vascular route of entry of Mycobacterium leprae into nerves. Once inside nerves, M leprae are ingested by Schwann cells, with a wide array of consequences. Axonal atrophy may occur early in this process; ultimately, affected nerves undergo segmental demyelination. Knowledge of the mechanisms of nerve injury in leprosy has been greatly limited by the minimal opportunities to study affected nerves in man. The nine-banded armadillo provides the only animal model of the pathogenesis of M leprae infection. New tools available for this model enable the study and correlation of events occurring in epidermal nerve fibers, dermal nerves, and nerve trunks, including neurophysiologic parameters, bacterial load, and changes in gene transcription in both neural and inflammatory cells. The armadillo model is likely to enhance understanding of the mechanisms of nerve injury in leprosy and offers a means of testing proposed interventions.

Up-regulation of cutaneous α1 -adrenoceptors in complex regional pain syndrome type I.

In a small radioligand-binding study of cutaneous α1 -adrenoceptors in complex regional pain syndrome (CRPS), signal intensity was greater in the CRPS-affected limb than in controls. However, it was not possible to localize heightened expression of α1 -adrenoceptors to nerves, sweat glands, blood vessels, or keratinocytes using this technique. To explore this in the present study, skin biopsies were obtained from 31 patients with CRPS type I and 23 healthy controls of similar age and sex distribution. Expression of α1 -adrenoceptors on keratinocytes and on dermal blood vessels, sweat glands, and nerves was assessed using immunohistochemistry. α1 -Adrenoceptors were expressed more strongly in dermal nerve bundles and the epidermis both on the affected and contralateral unaffected side in patients than in controls (P<0.05). However, expression of α1 -adrenoceptors in sweat glands and blood vessels was similar in patients and controls. α1 -Adrenoceptor staining intensity in the CRPS-affected epidermis was associated with pain intensity (P < 0.05), but a similar trend for nerve bundles did not achieve statistical significance. Epidermal cells influence nociception by releasing ligands that act on sensory nerve fibers. Moreover, an increased expression of α1 -adrenoceptors on nociceptive afferents has been shown to aggravate neuropathic pain. Thus, the heightened expression of α1 -adrenoceptors in dermal nerves and epidermal cells might augment pain and neuroinflammatory disturbances after tissue injury in patients with CRPS type I.

The relationship of nerve fibre pathology to sensory function in entrapment neuropathy.

Surprisingly little is known about the impact of entrapment neuropathy on target innervation and the relationship of nerve fibre pathology to sensory symptoms and signs. Carpal tunnel syndrome is the most common entrapment neuropathy; the aim of this study was to investigate its effect on the morphology of small unmyelinated as well as myelinated sensory axons and relate such changes to somatosensory function and clinical symptoms. Thirty patients with a clinical and electrophysiological diagnosis of carpal tunnel syndrome [17 females, mean age (standard deviation) 56.4 (15.3)] and 26 age and gender matched healthy volunteers [18 females, mean age (standard deviation) 51.0 (17.3)] participated in the study. Small and large fibre function was examined with quantitative sensory testing in the median nerve territory of the hand. Vibration and mechanical detection thresholds were significantly elevated in patients with carpal tunnel syndrome (P<0.007) confirming large fibre dysfunction and patients also presented with increased thermal detection thresholds (P<0.0001) indicative of C and Aδ-fibre dysfunction. Mechanical and thermal pain thresholds were comparable between groups (P>0.13). A skin biopsy was taken from a median nerve innervated area of the proximal phalanx of the index finger. Immunohistochemical staining for protein gene product 9.5 and myelin basic protein was used to evaluate morphological features of unmyelinated and myelinated axons. Evaluation of intraepidermal nerve fibre density showed a striking loss in patients (P<0.0001) confirming a significant compromise of small fibres. The extent of Meissner corpuscles and dermal nerve bundles were comparable between groups (P>0.07). However, patients displayed a significant increase in the percentage of elongated nodes (P<0.0001), with altered architecture of voltage-gated sodium channel distribution. Whereas neither neurophysiology nor quantitative sensory testing correlated with patients' symptoms or function deficits, the presence of elongated nodes was inversely correlated with a number of functional and symptom related scores (P<0.023). Our findings suggest that carpal tunnel syndrome does not exclusively affect large fibres but is associated with loss of function in modalities mediated by both unmyelinated and myelinated sensory axons. We also document for the first time that entrapment neuropathies lead to a clear reduction in intraepidermal nerve fibre density, which was independent of electrodiagnostic test severity. The presence of elongated nodes in the target tissue further suggests that entrapment neuropathies affect nodal structure/myelin well beyond the focal compression site. Interestingly, nodal lengthening may be an adaptive phenomenon as it inversely correlates with symptom severity.

Spontaneous multicentric myxoma of the dermal nerve sheaths in farmed European eels Anguilla anguilla.

This report describes a peripheral nerve sheath tumour in 8 European eels Anguilla anguilla L. from a fish farm located in Croatia. The newborn tissue appeared as smooth and soft skin nodules without pronounced colour change. Nodules were dome-shaped with a pale crater and were present on different body areas. In general, nodules were located as series of differently sized protrusions extending along the lateral line on both sides of the fish, as well as sensory canals on the head. Cut sections showed a homogeneous, pale white-grey texture. Histologically, the pathological tissue was located in the dermis, occasionally intruding into the hypodermis, and pushing as a space-occupying mass against the underlying muscle tissue without any evident boundaries. The pressure also caused changes in the overlying epidermis, such as atrophy, spongiosis and erosion. In some areas, the epidermis was 1 cell thick and club and goblet cells had completely disappeared. Ultimately, these changes resulted in shallow ulceration. Tumour tissue was characterized by a scant population of spindle or stellate cells, with oval, hyperchromatic nuclei and pale cytoplasm embedded in a copious myxoid matrix. Cells were arranged in fascicles and whorls, extending in a poorly defined manner among the dermal collagen bundles. Occasionally, adipose cells were also detected, mainly in the central portion of the bulges. Myxoid areas appeared rich in metachromatic and alcianophilic mucous ground substance. Reticular fibres and collagenous connective tissue were scarce. Immunohistochemistry (IHC) using antibodies against S-100 and glial fibrillary acidic protein caused a slight positive reaction in neoplastic dendritic cells. High magnification showed the immunostaining to be cytoplasmic in all tumour cells. IHC with anti-calretinin antibody gave only negative results. Macroscopic, histological, histochemical and immunohistochemical findings were consistent with a diagnosis of multicentric myxoma of the dermal nerve sheaths, a tumour not yet reported in fish.

Neuropathic pain in two-generation twins carrying the sodium channel Nav1.7 functional variant R1150W

We present clinical, neuropathological, and molecular genetic findings of a family with a new pain phenotype of the sodium channel gene SCN9A polymorphism R1150W. A 46-year-old woman presented with a 5-year history of episodic temperature- and exercise-dependent burning pain of the feet and lower legs associated with numbness of the distal upper and lower limbs. Her monozygotic twin sister and their mother and her twin presented similar symptoms. Clinical evaluation was normal except for a mild distal sensory deficit in fingers and feet. Electrophysiological testing was unremarkable, as were serum and cerebrospinal fluid laboratory findings. Skin biopsies of the distal lower limbs revealed an epidermal nerve fiber density at the lower limit of normal. Myelinated dermal nerve fibers showed elongated nodes of Ranvier, but normal distribution of nodal and paranodal proteins. Genetic testing for ion channel-associated pain disorders revealed an amino acid R1150W substitution of the Nav1.7 sodium channel. The combination of a Nav1.7 polymorphism with dysmyelinating features in small-caliber peripheral nerves has not been described before and may suggest an explanation for the clinical syndrome in our patients. Treatment with the sodium channel blocker lamotrigine provided some relief, consistent with a role of sodium channel dysfunction in the pain syndrome of this family.

Cutaneous neuropathy in Parkinson's disease: a window into brain pathology.

The deposition of alpha-synuclein in the brain, the neuropathological hallmark of Parkinson’s disease (PD), follows a distinct anatomical and temporal sequence. This study aimed to characterize alpha-synuclein deposition in cutaneous nerves from patients with PD. We further strived to explore whether peripheral nerve involvement is intrinsic to PD and reflective of known features of brain pathology, which could render it a useful tool for pathogenetic studies and pre-mortem histological diagnosis of PD. We obtained skin biopsies from the distal and proximal leg, back and finger of 31 PD patients and 35 controls and quantified the colocalization of phosphorylated alpha-synuclein in somatosensory and autonomic nerve fibers and the pattern of loss of different subtypes of dermal fibers. Deposits of phosphorylated alpha-synuclein were identified in 16/31 PD patients but in 0/35 controls (p < 0.0001). Quantification of nerve fibers revealed two types of peripheral neurodegeneration in PD: (1) a length-dependent reduction of intraepidermal small nerve fibers (p < 0.05) and (2) a severe non-length-dependent reduction of substance P-immunoreactive intraepidermal nerve fibers (p < 0.0001). The latter coincided with a more pronounced proximal manifestation of alpha-synuclein pathology in the skin. The histological changes did not correlate with markers of levodopa toxicity such as vitamin B12 deficiency. Our findings suggest that loss of peripheral nerve fibers is an intrinsic feature of PD and that peripheral nerve changes may reflect the two types of central alpha-synuclein-related PD pathology, namely neuronal death and axonal degeneration. Detection of phosphorylated alpha-synuclein in dermal nerve fibers might be a useful diagnostic test for PD with high specificity but low sensitivity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1284-0) contains supplementary material, which is available to authorized users.

Neuropathic truncal pain in patients with type 2 diabetes mellitus relieved by topical cream and nerve block

Neuropathic truncal pain in patients with type 2 diabetes mellitus relieved by topical cream and nerve block

Neurothekoma of orbit

Myxoid neurothekeoma, also known as dermal nerve sheath myxoma, is a rare tumor of presumed nerve sheath origin, which affects adolescents and young adults. A middle-aged woman came with the complaint of inferior displacement of left eyeball for 4 years. She was diagnosed previously as pseudotumor and treated with systemic steroids twice before, following which symptoms were relieved for short duration. There is a history of ptosis surgery done in childhood. Orbit examination showed firm, nonmovable, nonreducible mass below superior orbital margin. Computed tomography scan of orbit showed a round well-circumscribed, isodense mass located in the suprabulbar extraconal space. Surgical excision of mass through anterior orbitotomy was performed. One large size nodule with rest small daughter nodules was removed. Histopathological examination revealed myxoid lobules and fascicles of spindle cells with no atypia, suggestive of nerve sheath myxoma. It is so far rarest tumor in the orbit.

Upregulation of α1-adrenoceptors on cutaneous nerve fibres after partial sciatic nerve ligation and in complex regional pain syndrome type II

After peripheral nerve injury, nociceptive afferents acquire an abnormal excitability to adrenergic agents, possibly due to an enhanced expression of α1-adrenoceptors (α1-ARs) on these nerve fibres. To investigate this in the present study, changes in α1-AR expression on nerve fibres in the skin and sciatic nerve trunk were assessed using immunohistochemistry in an animal model of neuropathic pain involving partial ligation of the sciatic nerve. In addition, α1-AR expression on nerve fibres was examined in painful and unaffected skin of patients who developed complex regional pain syndrome (CRPS) after a peripheral nerve injury (CRPS type II). Four days after partial ligation of the sciatic nerve, α1-AR expression was greater on dermal nerve fibres that survived the injury than on dermal nerve fibres after sham surgery. This heightened α1-AR expression was observed on nonpeptidergic nociceptive afferents in the injured sciatic nerve, dermal nerve bundles, and the papillary dermis. Heightened expression of α1-AR in dermal nerve bundles after peripheral nerve injury also colocalized with neurofilament 200, a marker of myelinated nerve fibres. In each patient examined, α1-AR expression was greater on nerve fibres in skin affected by CRPS than in unaffected skin from the same patient or from pain-free controls. Together, these findings provide compelling evidence for an upregulation of α1-ARs on cutaneous nociceptive afferents after peripheral nerve injury. Activation of these receptors by circulating or locally secreted catecholamines might contribute to chronic pain in CRPS type II.

TRPA1-Dependent Pruritus in IL-13–Induced Chronic Atopic Dermatitis

Chronic debilitating pruritus is a cardinal feature of atopic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In this study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13-transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from healthy subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1(+) dermal afferent nerves and TRPA1(+) mast cells in a Th2-dominated inflammatory environment.

Increased Expression of Cutaneous α1-Adrenoceptors After Chronic Constriction Injury in Rats

α1-Adrenoceptor expression on nociceptors may play an important role in sympathetic-sensory coupling in certain neuropathic pain syndromes. The aim of this study was to determine whether α1-adrenoceptor expression was upregulated on surviving peptidergic, nonpeptidergic, and myelinated nerve fiber populations in the skin after chronic constriction injury of the sciatic nerve in rats. Seven days after surgery, α1-adrenoceptor expression was upregulated in the epidermis and on dermal nerve fibers in plantar skin ipsilateral to the injury but not around blood vessels. This α1-adrenoceptor upregulation in the plantar skin was observed on all nerve fiber populations examined. However, α1-adrenoceptor expression was unaltered in the dorsal hind paw skin after the injury. The increased expression of α1-adrenoceptors on cutaneous nociceptors in plantar skin after chronic constriction injury suggests that this may be a site of sensory-sympathetic coupling that increases sensitivity to adrenergic agonists after nerve injury. In addition, activation of upregulated α1-adrenoceptors in the epidermis might cause release of factors that stimulate nociceptive signaling. PerspectiveOur findings indicate that peripheral nerve injury provokes upregulation of α1-adrenoceptors on surviving nociceptive afferents and epidermal cells in the skin. This might contribute to sympathetically maintained pain in conditions such as complex regional pain syndrome, painful diabetic neuropathy, and postherpetic neuralgia.