Cutaneous pain in disorders affecting peripheral nerves

Stucky, Cheryl L.; Mikesell, Alexander R.

doi:10.1016/j.neulet.2021.136233

Cited by 18 publications

(9 citation statements)

References 253 publications

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“…Recent evidence suggests that infiltrating immune cells can facilitate direct neuro-immune interactions ( 104 ). Interestingly, Shepherd et al demonstrated that activation of the angiotensin II receptor on skin macrophages and consequent TRPA1 activation on sensory nerves is correlated with mechanical hypersensitivity and pain sensation ( 105 ).…”

Section: Mechanistic Insight Into Cipn Related Neuropathic Painmentioning

confidence: 99%

A mechanistic understanding of the relationship between skin innervation and chemotherapy-induced neuropathic pain

Meregalli

Monza²,

Jongen³

2022

Front. Pain Res.

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Neuropathic pain is a frequent complication of chemotherapy-induced peripheral neurotoxicity (CIPN). Chemotherapy-induced peripheral neuropathies may serve as a model to study mechanisms of neuropathic pain, since several other common causes of peripheral neuropathy like painful diabetic neuropathy may be due to both neuropathic and non-neuropathic pain mechanisms like ischemia and inflammation. Experimental studies are ideally suited to study changes in morphology, phenotype and electrophysiologic characteristics of primary afferent neurons that are affected by chemotherapy and to correlate these changes to behaviors reflective of evoked pain, mainly hyperalgesia and allodynia. However, hyperalgesia and allodynia may only represent one aspect of human pain, i.e., the sensory-discriminative component, while patients with CIPN often describe their pain using words like annoying, tiring and dreadful, which are affective-emotional descriptors that cannot be tested in experimental animals. To understand why some patients with CIPN develop neuropathic pain and others not, and which are the components of neuropathic pain that they are experiencing, experimental and clinical pain research should be combined. Emerging evidence suggests that changes in subsets of primary afferent nerve fibers may contribute to specific aspects of neuropathic pain in both preclinical models and in patients with CIPN. In addition, the role of cutaneous neuroimmune interactions is considered. Since obtaining dorsal root ganglia and peripheral nerves in patients is problematic, analyses performed on skin biopsies from preclinical models as well as patients provide an opportunity to study changes in primary afferent nerve fibers and to associate these changes to human pain. In addition, other biomarkers of small fiber damage in CIPN, like corneal confocal microscope and quantitative sensory testing, may be considered.

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Section: Mechanistic Insight Into Cipn Related Neuropathic Painmentioning

confidence: 99%

A mechanistic understanding of the relationship between skin innervation and chemotherapy-induced neuropathic pain

Meregalli

Monza²,

Jongen³

2022

Front. Pain Res.

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“…Cutaneous nerve fiber degeneration and sensitization are hallmarks of small fiber pathology; however, the underlying pathomechanisms are unclear ( Üçeyler, 2016 ). The impact of skin cells on nociceptive and non-nociceptive stimulus detection is increasingly recognized ( Lumpkin and Caterina, 2007 ; Stucky and Mikesell, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Interaction of human keratinocytes and nerve fiber terminals at the neuro-cutaneous unit

Erbacher,

Britz,

Dinkel

et al. 2024

eLife

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Traditionally, peripheral sensory neurons are assumed as the exclusive transducers of external stimuli. Current research moves epidermal keratinocytes into focus as sensors and transmitters of nociceptive and non-nociceptive sensations, tightly interacting with intraepidermal nerve fibers at the neuro-cutaneous unit. In animal models, epidermal cells establish close contacts and ensheath sensory neurites. However, ultrastructural morphological and mechanistic data examining the human keratinocyte-nerve fiber interface are sparse. We investigated this exact interface in human skin applying super-resolution array tomography, expansion microscopy, and structured illumination microscopy. We show keratinocyte ensheathment of afferents and adjacent connexin 43 contacts in native skin and have applied a pipeline based on expansion microscopy to quantify these parameter in skin sections of healthy participants versus patients with small fiber neuropathy. We further derived a fully human co-culture system, visualizing ensheathment and connexin 43 plaques in vitro. Unraveling human intraepidermal nerve fiber ensheathment and potential interaction sites advances research at the neuro-cutaneous unit. These findings are crucial on the way to decipher the mechanisms of cutaneous nociception.

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“…Thus, whether these models accurately reflect the cellular and molecular mechanisms involved in removal of axonal debris in mature, stratified skin remains unknown. Identification of the phagocytes involved in debris removal in the adult epidermis is relevant for understanding post-embryonic pathologies in which axon homeostasis is altered, such as diabetic and chemotherapy-induced peripheral neuropathy ( Stucky and Mikesell, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Zebrafish cutaneous injury models reveal that Langerhans cells engulf axonal debris in adult epidermis

Peterman

Quitevis

Black

et al. 2023

Disease Models &Amp; Mechanisms

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Somatosensory neurons extend enormous peripheral axons to the skin, where they detect diverse environmental stimuli. Somatosensory peripheral axons are easily damaged due to their small caliber and superficial location. Axonal damage results in Wallerian degeneration, creating vast quantities of cellular debris that phagocytes must remove to maintain organ homeostasis. The cellular mechanisms that ensure efficient clearance of axon debris from stratified adult skin are unknown. Here, we establish zebrafish scales as a tractable model to study axon degeneration in the adult epidermis. Using this system, we demonstrate that skin-resident immune cells known as Langerhans cells engulf the majority of axon debris. In contrast to immature skin, adult keratinocytes do not significantly contribute to debris removal, even in animals lacking Langerhans cells. Our study establishes a powerful new model for studying Wallerian degeneration and identifies a new function for Langerhans cells in maintenance of adult skin homeostasis following injury. These findings have important implications for pathologies that trigger somatosensory axon degeneration.

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Cutaneous pain in disorders affecting peripheral nerves

Cited by 18 publications

References 253 publications

A mechanistic understanding of the relationship between skin innervation and chemotherapy-induced neuropathic pain

A mechanistic understanding of the relationship between skin innervation and chemotherapy-induced neuropathic pain

Interaction of human keratinocytes and nerve fiber terminals at the neuro-cutaneous unit

Zebrafish cutaneous injury models reveal that Langerhans cells engulf axonal debris in adult epidermis

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