Project 1: Human Models of Chronic Itch
Project Managers:
Prof. Dr. R. Rukwied
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About:
Ongoing itch and pain are the key concerns of patients with chronic itch or pain conditions, but acute experimental models induce itch and therefore do not sufficiently reflect the clinical pathophysiology of patients. We will therefore establish experimental contact eczema as chronic itch model in volunteers using diphencyprone. This model provides localized inflammatory ongoing itch that is ideally suited to study changes of neuronal sensitivity, local mediator concentrations and expression patterns in a controlled fashion. As the development of inflammation and itch differ we will be able to take biopsies at a time with maximum itch and another when the inflammation peaks. At the peak of the spontaneous itch we will assess the level of a lipid mediator lysophosphatidylic acid (LPA) using dermal microdialysis. The microdialysis technique has been refined to optimize recovery for lipid mediators by with large pore size membrane, a stop flow paradigm and addition of cyclodextrane into the perfusate.
We have learned from chronic pain that beyond the acute excitatory effects of inflammatory mediators, long term neuronal sensitization can increase neuronal excitability a process termed “hyperalgesic priming” that has been shown for nerve growth factor (NGF). NGF is known to sensitize nociceptors in a supra additive way in the UV-B irradiation model and clinically, anti-NGF strategies have been proven to be analgesic and anti-pruritic. We will therefore test the hypothesis that NGF will also sensitize nociceptors to pruritics such as beta-Alanin, BAM8-22, LPA and IL-31. Moreover, we will use the pre-sensitization with NGF to test whether the itch sensation in the experimental eczema model will be increased even though the inflammation is supposed to be identical. In addition to the assessment of ongoing itch in this model we will make use of a newly developed C-fiber specific electrical stimulation paradigm that differentially activates C-nociceptor classes. It uses slow depolarizing ramps and will be applied to test for supra-threshold encoding and the ability of nociceptors to generate action potentials for prolonged periods as seen clinically. The same stimulation protocol will be used as paradigm for all the clinical projects in the consortium, but also in electrophysiological validation studies.
In summary, this project investigates the direct excitatory effects of inflammatory mediators, but also the effect of the neurotrophin NGF that is mainly increasing the ability of nociceptors to provide long lasting discharge. When acting in synergy, these two mechanisms are supposed to determine the level of clinical itch.
We have learned from chronic pain that beyond the acute excitatory effects of inflammatory mediators, long term neuronal sensitization can increase neuronal excitability a process termed “hyperalgesic priming” that has been shown for nerve growth factor (NGF). NGF is known to sensitize nociceptors in a supra additive way in the UV-B irradiation model and clinically, anti-NGF strategies have been proven to be analgesic and anti-pruritic. We will therefore test the hypothesis that NGF will also sensitize nociceptors to pruritics such as beta-Alanin, BAM8-22, LPA and IL-31. Moreover, we will use the pre-sensitization with NGF to test whether the itch sensation in the experimental eczema model will be increased even though the inflammation is supposed to be identical. In addition to the assessment of ongoing itch in this model we will make use of a newly developed C-fiber specific electrical stimulation paradigm that differentially activates C-nociceptor classes. It uses slow depolarizing ramps and will be applied to test for supra-threshold encoding and the ability of nociceptors to generate action potentials for prolonged periods as seen clinically. The same stimulation protocol will be used as paradigm for all the clinical projects in the consortium, but also in electrophysiological validation studies.
In summary, this project investigates the direct excitatory effects of inflammatory mediators, but also the effect of the neurotrophin NGF that is mainly increasing the ability of nociceptors to provide long lasting discharge. When acting in synergy, these two mechanisms are supposed to determine the level of clinical itch.
Related Publications
- Obreja O, Kluschina O, Mayer A, Hirth M, Schley M, Schmelz M, Rukwied R. NGF enhances electrically induced pain, but not axon reflex sweating. Pain 2011;152(8):1856-1863.
- Roggenkamp D, Falkner S, Stab F, Petersen M, Schmelz M, Neufang G. Atopic keratinocytes induce increased neurite outgrowth in a coculture model of porcine dorsal root ganglia neurons and human skin cells. J Invest Dermatol 2012;132(7):1892-1900.
- Roggenkamp D, Kopnick S, Stab F, Wenck H, Schmelz M, Neufang G. Epidermal nerve fibers modulate keratinocyte growth via neuropeptide signaling in an innervated skin model. J Invest Dermatol 2013;133(6):1620-1628.
- Rukwied R, Mayer A, Kluschina O, Obreja O, Schley M, Schmelz M. NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 2010;148(3):407-413.
- Rukwied R, Weinkauf B, Main M, Obreja O, Schmelz M. Axonal hyperexcitability after combined NGF sensitization and UV-B inflammation in humans. Eur J Pain 2013:10-2149.
- Rukwied R, Weinkauf B, Main M, Obreja O, Schmelz M. Inflammation meets sensitization--an explanation for spontaneous nociceptor activity? Pain 2013;154:2707-2714.
- Rukwied R, Main M, Weinkauf B, Schmelz M. NGF sensitizes nociceptors for cowhage- but not histamine-induced itch in human skin. J Invest Dermatol 2013;133:268-270.
- Weinkauf B, Dusch M, van der Ham J, Benrath J, Ringkamp M, Schmelz M, Rukwied R. Mechano-sensitive nociceptors are required to detect heat pain thresholds and cowhage itch in human skin. Eur J Pain 2016;20:215-222.
- Weinkauf B, Obreja O, Schmelz M, Rukwied R. Differential time course of NGF-induced hyperalgesia to heat versus mechanical and electrical stimulation in human skin. Eur J Pain 2015;19:789-796.
- Weinkauf B, Rukwied R, Quiding H, Dahllund L, Johansson P, Schmelz M. Local Gene Expression Changes after UV-Irradiation of Human Skin. PLoSONE 2012;7:e39411.