Ruprecht-Karls-Universität Heidelberg
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Rukwied0118 - Scientist (f/m) / PhD position
Project no:
Rukwied0118

Project leader:

Project supervisor:
Rukwied, Roman
Application deadline:
1. Jul 2018
Start of PhD project:
1. Aug 2018

Project description:

Title:
Selective activation of nociceptor sub-groups s by slowly depolarizing electrical stimuli
Summary:
Major complaints of patients with chronic neuropathic pain are spontaneous pain and excruciating pain upon supra-threshold stimulation. Mutations of the voltage-gated sodium channels NaV 1.7, 1.8 und 1.9 were identified as one mechanism associated with the generation and maintenance of neuropathic pain conditions. “Gain-of-function mutations” of these channels enhance action potential discharges upon electrical slow depolarization stimuli and provoke spontaneous activity [1]. Extracellular single nerve fiber recordings of unmyelinated nociceptors in patients suffering chronic neuropathic pain confirmed abnormal firing patterns and spontaneous discharges of particularly mechanically insensitive C-nociceptors [2]. In this project we will validate an electrical stimulation protocol of slowly depolarizing transcutaneously delivered stimuli to selectively activate unmyelinated afferent C-fibers. Slowly depolarization ramp currents cause the preferential opening of sodium channels NaV1.7, 1.8 or 1.9 and thus are nociceptor-specific. Single nerve-fiber recordings in the pig in vivo will be used to electro-physiologically validate the activation of different nociceptor classes. The involvement of sub-groups of voltage-gated sodium channels will be examined by NaV-modulating agents, e.g. the buffer-fish tetrodotoxin TTX, the cone snail peptide conotoxin, the sea-anemone toxin ATX-II, or the tarantula venom ProTx-II. Compound action potentials will be recorded from isolated nerve fascicles of pig and mouse in vitro with stimulation protocols identical to those from the in vivo studies in order to validate a synchronized C-nociceptor activation. Sub-groups of sodium channels contributing to the compound action potential generation by slowly depolarizing ramp currents will be investigated by adding toxins (e.g. TTX, ProTx-II, conotoxin ATX-II) to the perfusate of the in vitro preparation.
References:
[1] Han C, Vasylyev D, Macala LJ, Gerrits MM, Hoeijmakers JG, Bekelaar KJ, Dib-Hajj SD, Faber CG, Merkies IS, Waxman SG. The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability. J Neurol Neurosurg Psychiatry 2014;85(5):499-505.

[2] Kleggetveit IP, Namer B, Schmidt R, Helas T, Ruckel M, ORstavik K, Schmelz M, Jorum E. High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain 2012;153(10):2040-2047.
Methods that will be used:
Extracellular nerve terminal recordings in vivo
Compound action potential recordings in vitro
Cooperation partners:
Prof. Martin Schmelz and PD Richard Carr, Medical Faculty Mannheim, Heidelberg
Personal qualifications:
A bachelor’s degree in natural sciences (physics, biology or chemistry), medicine or veterinary medicine is required. Ideally, candidates have experience in electro-physiology preparation and show interests in neuroscience and patho-physiology. Requisite training for each of the techniques will be provided during the candidature.
Keywords:
Nociception, axonal excitability, voltage-gated sodium channels