Starts:

Thursday, September 22nd
4:30pm-6:00pm EDT

Category:

Topical Workshop

Tracks:

Mechanisms

Room

716 B

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Which Structural and Functional Changes in Skin Nociceptors Cause Chronic Pain?

The key question of this topical workshop is which neuropathic changes in epidermal nociceptors can lead to chronic pain and how can we specifically assess the underlying changes in excitability. Beyond mere nerve fiber reduction as a frequent hallmark of small fiber neuropathy (SFN), we propose to look into which cues facilitate or inhibit epidermal innervation or re-innervation, and how the resulting structural and functional changes of epidermal nerve fibres can contribute to pain. Moreover, test paradigms that specifically assess the clinically relevant hyperexcitability of nociceptors are lacking as conventional sensory testing is mainly based on pain threshold. Dr. Margarita Calvo will show how dysfunction of keratinocytes is in part the cause of lack of epidermal reinnervation, maintaining epidermal fiber damage, both in patients with epidermolysis bullosa and in a preclinical model of SFN. Dr. Nurcan Üçeyler will discuss a potential role of axon guidance mechanisms in SFN and fibromyalgia for the pathophysiology of nerve fiber de-/regeneration and pain in these patients. Finally, Dr. Schmelz will present C-fiber specific electrical stimulation paradigms that differentially activate skin nociceptor subpopulations and detect activity-dependent hyperexcitability in neuropathic pain patients.

Presentations

Time
4:30pm EDT–6:00pm EDT

Axon Guidance Cues That May Play a Role in the Development of Small Fiber Pathology

Tracks: Mechanisms
Categories: Topical Workshop
Presented By: Professor Nurcan Üçeyler

Neuropathic pain may be caused by diverse etiologies and that the same etiology may lead to a painful condition or remain painless. Skin punch biopsy is increasingly used to determine intraepidermal nerve fiber density (IENFD). Although not specific, a reduction of IENFD is a frequent finding in conditions with small fiber pathology. The question is, how intraepidermal nerve fibers may be directed in growth and if peripheral mechanisms may play a role that could be used as surrogates or even future preventive and therapeutic targets. Axon guides are cues that have been hardly investigated in the peripheral nervous system, but that bear the potential to attract and/or repel peripheral axons. Here, the audience will learn about selected axon guides that may play a role in the development of small fiber pathology. Current knowledge will be summarized focusing on patient-derived biomaterial and in vitro model systems to better understand this exciting research field.

4:30pm EDT–6:00pm EDT

C-fiber Specific Electrical Stimulation Paradigms that Differentially Activate Skin Nociceptor Subpopulations and Detect Activity-Dependent

Tracks: Mechanisms
Categories: Topical Workshop
Presented By: Professor Martin Schmelz

In this presentation slow depolarizing electrical stimuli will be presented that selectively active polymodal and mechano-insensitive nociceptors in human skin as validated by human microneurography and axon reflex erythema. While electrical pain thresholds to such stimuli mainly reflect the level of small fiber neuropathy, tonic stimulation reveals differences between painful and painless neuropathy. While stimulation in normal skin of healthy volunteers and non-painful skin areas leads to adaptation of pain ratings there is increasing pain upon such tonic stimulation in the painful area. Mechanistic underpinnings of this activity-dependent changes of excitability will be presented including inactivation of sodium channels, after-hyperpolarization and depolarizing chloride currents. Direct links between geometry of sensory endings in the epidermis to excitability will be presented, in-particular branching patterns and axonal swelling. Implications and limitations of evoked sensory tests to probe nociceptor excitability under normal conditions and in neuropathic pain will be discussed.

4:30pm EDT–6:00pm EDT

Dysfunction of Keratinocytes in Small Fiber Neuropathy is in Part the Cause of Lack of Epidermal Reinnervation

Tracks: Mechanisms
Categories: Topical Workshop
Presented By: Dr. Margarita Calvo

Fibers in the epidermis degenerate in pathological conditions, but once the insult is removed, they should grow back and completely reinnervate the epidermis (JCompNeurol 2003). However, this doesn’t occur in chronic SFN. In this presentation I will show data on a particular case of SFN-induced by a skin disease (Recessive Dystrophic Epidermolysis Bullosa or RDEB) where we have seen that neurotrophins that should guide the reinnervating axonal cone, failed to be secreted. We have observed that the skin of healthy volunteers increases their RNA/protein expression of NGF and GDNF at least 4-7 times after a skin scratch injury. However, RDEB patients with a secondary SFN, show no neurotrophins response following injury. In the epidermis the largest amount of neurotrophins comes from keratinocytes.  Interestingly, human keratinocytes from healthy subjects, but not from RDEB, increased their in vitro release of neurotrophins following scratch injury. Furthermore, conditioned medium from healthy keratinocytes, but not from RDEB keratinocytes, stimulate sensory neuron axonal growth in vitro. In an animal model of SFN induced by RDEB we have demonstrated that a topical treatment with neurotrophins receptor agonists could revert thermal hypoesthesia and reduced intraepidermal fibres. These findings give hope for a treatment of SFN-induced by skin conditions.

Presenters

Professor Nurcan Üçeyler

Professor of Neurology
University of Würzburg

Dr. Margarita Calvo

Associate professor
Pontificia Universidad Católica de Chile

Professor Martin Schmelz

Director
MCTN. Medical Faculty Mannheim, Heidelberg University