<scp>UVB</scp>‐ and<scp>NGF</scp>‐induced cutaneous sensitization in humans selectively augments cowhage‐ and histamine‐induced pain and evokes mechanical hyperknesis

Andersen, Hjalte Holm; Vecchio, Silvia Lo; Elberling, Jesper; Yosipovitch, Gil; Arendt-Nielsen, Lars

doi:10.1111/exd.13508

Cited by 13 publications

(13 citation statements)

References 69 publications

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“…Therefore, the increase in activity of keratinocytesensory neurons synaptic-like contacts may constitute a mechanism for peripheral sensitization of sensory neurons, leading to pain and itch perception. 54 Similarly, the increased epidermal expression of TRPV1 combined with a decrease of FNEs density in the elderly could question the implication of keratinocyte-sensory neuron synapticlike contacts in senile pruritus. 55,56 Keratinocytes and FNEs may act as a 2-receptor-site model, each conveying specific aspects of temperature, pain, and itch, 10,57 similar to Merkel cells 58 and the Aβ nerve fibers in the Merkel complexes.…”

Section: Discussionmentioning

confidence: 99%

Keratinocytes Communicate with Sensory Neurons via Synaptic‐like Contacts

Talagas

Lebonvallet

Leschiera

et al. 2020

Annals of Neurology

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Objective: Pain, temperature, and itch are conventionally thought to be exclusively transduced by the intraepidermal nerve endings. Although recent studies have shown that epidermal keratinocytes also participate in sensory transduction, the mechanism underlying keratinocyte communication with intraepidermal nerve endings remains poorly understood. We sought to demonstrate the synaptic character of the contacts between keratinocytes and sensory neurons and their involvement in sensory communication between keratinocytes and sensory neurons. Methods: Contacts were explored by morphological, molecular, and functional approaches in cocultures of epidermal keratinocytes and sensory neurons. To interrogate whether structures observed in vitro were also present in the human epidermis, in situ correlative light electron microscopy was performed on human skin biopsies. Results: Epidermal keratinocytes dialogue with sensory neurons through en passant synaptic-like contacts. These contacts have the ultrastructural features and molecular hallmarks of chemical synaptic-like contacts: narrow intercellular cleft, keratinocyte synaptic vesicles expressing synaptophysin and synaptotagmin 1, and sensory information transmitted from keratinocytes to sensory neurons through SNARE-mediated (syntaxin1) vesicle release. Interpretation: By providing selective communication between keratinocytes and sensory neurons, synaptic-like contacts are the hubs of a 2-site receptor. The permanent epidermal turnover, implying a specific en passant structure and high plasticity, may have delayed their identification, thereby contributing to the long-held concept of nerve endings passing freely between keratinocytes. The discovery of keratinocyte-sensory neuron synaptic-like contacts may call for a reassessment of basic assumptions in cutaneous sensory perception and sheds new light on the pathophysiology of pain and itch as well as the physiology of touch.

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Section: Discussionmentioning

confidence: 99%

Keratinocytes Communicate with Sensory Neurons via Synaptic‐like Contacts

Talagas

Lebonvallet

Leschiera

et al. 2020

Annals of Neurology

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“…68 NGF is also shown to sensitize the skin to cowhage-induced itch 69 and contribute to mechanical hyperknesis. 70 Artemin, a member of the glial cell line-derived neurotrophic factors, is produced by SP-stimulated fibroblasts and keratinocytes in response to air pollutants. 71,72 Artemin decreases the threshold of heat-induced itch sensation.…”

Section: Neural Sensitization In the Skin And Sensory Neuronsmentioning

confidence: 99%

Itch: From mechanism to (novel) therapeutic approaches

Yosipovitch

Rosen

Hashimoto

2018

Journal of Allergy and Clinical Immunology

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260

307

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Itch is a common sensory experience that is prevalent in patients with inflammatory skin diseases, as well as in those with systemic and neuropathic conditions. In patients with these conditions, itch is often severe and significantly affects quality of life. Itch is encoded by 2 major neuronal pathways: histaminergic (in acute itch) and nonhistaminergic (in chronic itch). In the majority of cases, crosstalk existing between keratinocytes, the immune system, and nonhistaminergic sensory nerves is responsible for the pathophysiology of chronic itch. This review provides an overview of the current understanding of the molecular, neural, and immune mechanisms of itch: beginning in the skin, proceeding to the spinal cord, and eventually ascending to the brain, where itch is processed. A growing understanding of the mechanisms of chronic itch is expanding, as is our pipeline of more targeted topical and systemic therapies. Our therapeutic armamentarium for treating chronic itch has expanded in the last 5 years, with developments of topical and systemic treatments targeting the neural and immune systems.

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“…82 Likewise, intradermal injection of NGF produces long-lasting local thermal (early onset) and mechanical (delayed) hyperalgesia. [83][84][85][86][87] Localized priming of nociceptors following intradermal injection of NGF has also been demonstrated through an enhancement of hyperalgesia in response to irradiation with ultraviolet-B. 88,89 Intramuscular injection of NGF has been shown to cause lasting mechanical hyperalgesia in a variety of muscles.…”

Section: Ngf Administration Induces Hyperalgesiamentioning

confidence: 99%

<p>Nerve Growth Factor Signaling and Its Contribution to Pain</p>

Barker¹,

Mantyh²,

Arendt-Nielsen³

et al. 2020

JPR

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154

104

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Nerve growth factor (NGF) is a neurotrophic protein essential for the growth, differentiation, and survival of sympathetic and sensory afferent neurons during development. A substantial body of evidence, based on both animal and human studies, demonstrates that NGF plays a pivotal role in modulation of nociception in adulthood. This has spurred development of a variety of novel analgesics that target the NGF signaling pathway. Here, we present a narrative review designed to summarize how NGF receptor activation and downstream signaling alters nociception through direct sensitization of nociceptors at the site of injury and changes in gene expression in the dorsal root ganglion that collectively increase nociceptive signaling from the periphery to the central nervous system. This review illustrates that NGF has a well-known and multifunctional role in nociceptive processing, although the precise signaling pathways downstream of NGF receptor activation that mediate nociception are complex and not completely understood. Additionally, much of the existing knowledge derives from studies performed in animal models and may not accurately represent the human condition. However, available data establish a role for NGF in the modulation of nociception through effects on the release of inflammatory mediators, nociceptive ion channel/receptor activity, nociceptive gene expression, and local neuronal sprouting. The role of NGF in nociception and the generation and/or maintenance of chronic pain has led to it becoming a novel and attractive target of pain therapeutics for the treatment of chronic pain conditions.

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UVB‐ andNGF‐induced cutaneous sensitization in humans selectively augments cowhage‐ and histamine‐induced pain and evokes mechanical hyperknesis

Cited by 13 publications

References 69 publications

Keratinocytes Communicate with Sensory Neurons via Synaptic‐like Contacts

Keratinocytes Communicate with Sensory Neurons via Synaptic‐like Contacts

Itch: From mechanism to (novel) therapeutic approaches

<p>Nerve Growth Factor Signaling and Its Contribution to Pain</p>

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