The epidermal nerve fibre network: characterization of nerve fibres in human skin by confocal microscopy and assessment of racial variations

Reilly, David; Ferdinando, Dudley; Johnston, Christopher; Shaw, C.; Buchanan, K.D.; Green, M.R.

doi:10.1046/j.1365-2133.1997.18001893.x

Cited by 94 publications

(65 citation statements)

References 32 publications

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“…Morphological correlates of functional desensitization after capsaicin application to skin are unknown. Although topical capsaicin decreased the number of nerve fibers in the epidermis as observed in a blister roof (Reilly et al, 1997), this was not verified by skin biopsy or sensory testing. Therefore, in this correlative study in humans, psychophysical measures of cutaneous sensation and immunohistochemical techniques were used to determine whether the hypalgesia after intradermal injection of capsaicin could be attributed to morphological changes in epidermal nerve fibers (ENFs).…”

Section: Abstract: Pain; Analgesia; Protein Gene Product 95; Intracmentioning

confidence: 98%

Intradermal Injection of Capsaicin in Humans Produces Degeneration and Subsequent Reinnervation of Epidermal Nerve Fibers: Correlation with Sensory Function

Simone¹,

et al. 1998

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The ability of capsaicin to excite and subsequently to desensitize a select group of small sensory neurons has made it a useful tool to study their function. For this reason, application of capsaicin to the skin has been used for a variety of painful syndromes. We examined whether intradermal injection of capsaicin produced morphological changes in cutaneous nerve fibers that would account for its analgesic properties by comparing cutaneous innervation in capsaicin-treated skin with psychophysical measures of sensation. At various times after capsaicin injection, nerve fibers were visualized immunohistochemically in skin biopsies and were quantified. In normal skin the epidermis is heavily innervated by nerve fibers immunoreactive for protein gene product (PGP) 9.5, whereas fibers immunoreactive for substance P (SP) and calcitonin gene-related peptide (CGRP) are typically associated with blood vessels. There was nearly complete degeneration of epidermal nerve fibers and the subepidermal neural plexus in capsaicin-treated skin, as indicated by the loss of immunoreactivity for PGP 9.5 and CGRP. The effect of capsaicin on dermal nerve fibers immunoreactive for SP was less obvious. Capsaicin decreased sensitivity to pain produced by sharp mechanical stimuli and nearly eliminated heat-evoked pain within the injected area. Limited reinnervation of the epidermis and partial return of sensation occurred 3 weeks after treatment; reinnervation of the epidermis was ϳ25% of normal, and sensation improved to 50-75% of normal. These data show that sensory dysfunction after capsaicin application to the skin results from rapid degeneration of intracutaneous nerve fibers.

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Section: Abstract: Pain; Analgesia; Protein Gene Product 95; Intracmentioning

confidence: 98%

Intradermal Injection of Capsaicin in Humans Produces Degeneration and Subsequent Reinnervation of Epidermal Nerve Fibers: Correlation with Sensory Function

Simone¹,

et al. 1998

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“…In the skin, tachykinin-immunoreactive sensory nerves are often associated with dermal blood vessels, mast cells, hair follicles, or epidermal cells (671). Increased epidermal SP-immunoreactive nerve fibers have been observed in certain inflammatory human skin diseases such as psoriasis, atopic dermatitis, and contact dermatitis (reviewed in Refs.…”

Section: Tachykinins and Neurokinin Receptorsmentioning

confidence: 99%

“…With the use of electron microscopy (336), confocal laser scan microscopy (671), and immunohistochemistry (809), it is possible to demonstrate that the epidermis is also innervated by a three-dimensional network of unmyelinated C fibers with free-branching endings that arise in the dermis and their basement membrane apposed to epidermal cells such as keratinocytes, melanocytes, Langerhans cells, and Merkel cells, respectively. Increased epidermal innervation has been described in skin lesions of various inflammatory skin diseases (379,383,633,640,761,809), wound repair (234), skin cancer (232, 447,552,567,765), epithelial hyperplasia (702), after exposure to ultraviolet (UV) light, or during psoralen UVA therapy (525,785).…”

Section: A Neuroanatomy and Neurophysiology Of Cutaneous Nervesmentioning

confidence: 99%

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Roosterman¹,

Goerge

Schneider

et al. 2006

Physiological Reviews

548

521

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This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.

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“…Substance P (SP) 3 is one such neuropeptide that is widely distributed in the central and peripheral nervous system including the skin (2,3). SP is capable of inducing a number of inflammatory responses including vasodilatation, plasma extravasation, leukocyte activation, endothelial cell adhesion molecule expression, cellular cytokine production, and mast cell activation (4).…”

mentioning

confidence: 99%

Neutral Endopeptidase Terminates Substance P-Induced Inflammation in Allergic Contact Dermatitis

Scholzen

Steinhoff

Bonaccorsi

et al. 2001

The Journal of Immunology

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Sensory nerve-derived neuropeptides such as substance P demonstrate a number of proinflammatory bioactivities, but less is known about their role in inflammatory skin disease. The cell surface metalloprotease neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme. This study tests the hypothesis that the absence of NEP results in dysregulated inflammatory skin responses. The effector phase of allergic contact dermatitis (ACD) responses was examined in NEP−/− knockout and NEP+/+ wild-type mice and compared with the irritant contact dermatitis response in these animals. NEP was found to be normally immunolocalized in epidermal keratinocytes and dermal blood vessels. The ACD ear swelling response was 2.5-fold higher in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes. The augmented ACD response in NEP−/− animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with topical capsaicin. Similar to NEP−/− mice, the acute inhibition of NEP in NEP+/+ animals resulted in an augmented ACD response. In contrast to the ACD responses, little differences were observed in the irritant contact dermatitis response of NEP−/− compared with NEP+/+ animals after epicutaneous application of the skin irritants croton oil or SDS. Thus, these results indicate that NEP and cutaneous neuropeptides have a significant role in the pathogenesis of ACD.

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The epidermal nerve fibre network: characterization of nerve fibres in human skin by confocal microscopy and assessment of racial variations

Cited by 94 publications

References 32 publications

Intradermal Injection of Capsaicin in Humans Produces Degeneration and Subsequent Reinnervation of Epidermal Nerve Fibers: Correlation with Sensory Function

Intradermal Injection of Capsaicin in Humans Produces Degeneration and Subsequent Reinnervation of Epidermal Nerve Fibers: Correlation with Sensory Function

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Neutral Endopeptidase Terminates Substance P-Induced Inflammation in Allergic Contact Dermatitis

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