Heterosynaptische Langzeitpotenzierung im Rückenmark als Mechanismus der neurogenen Hyperalgesie
Final Report Abstract
The focus of this project was on the consequences of long-term potentiation of nociceptive signal processing in the spinal cord for pain perception in healthy human subjects (pain LTP). Pain LTP was quantified psychophysically using pain ratings to electrical and mechanical test stimuli, and electrophysiologically using pinprick-evoked potentials. We demonstrated that LTP is favoured over LTD when high frequency trains of electrical pulses (HFS) are applied to the surface of the skin via multicontact electrodes that cover a large skin area. Induction of pain LTP saturated after first to second HFS in healthy volunteers, and - in analogy to the hippocampus - impaired saturation properties may contribute to the transition from acute to chronic pain in patients. Using two selective nerve block techniques (capsaicin desensitization, nerve compression) we found that TRPV1-positive C-fibres are the main inducers of both homotopic and heterotopic pain LTP. TRPV1-positive A-fibres contribute substantially to the induction of heterotopic painlong-term potentiation. TRPV1-negative C-fibres induce a component of homotopic self-facilitation but not heterotopic pain-long-term potentiation. TRPV1-negative A-fibres are the main afferents mediating pinprick pain and hyperalgesia; however, they do not appear to contribute to the induction of pain-long-term potentiation. These findings show that distinct peripheral fibre classes mediate induction of long-term potentiation-like pain amplification, its spatial spread to adjacent skin (i.e. secondary hyperalgesia), and the resulting enhanced sensitivity to pinprick in humans. Pain LTP could be partly prevented by hydrocortisone or cold-pressor induced stress but not by duloxetine, and it could be reversed by sedation with propofol and remifentanil. In most subjects, pain LTP reverts to normal within a day, but in a subgroup of 20% of healthy subjects a single conditioning episode of 5x1s 100 Hz HFS led to persistent pain LTP that is reminiscent of late LTP. These subjects may be at risk to develop chronic pain syndromes. In summary, we characterized the induction properties for LTP-like pain amplification in humans, studied risk factors for the transition between early and late LTP and identified interventions for the prevention and reversal of pain LTP.
Publications
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(2011) Analysis of hyperalgesia time courses in humans after painful electrical high-frequency stimulation identifies a possible transition from early to late LTP-like pain plasticity. Pain 152: 1532-1539
Pfau DB, Klein T, Putzer D, Pogatzki-Zahn EM, Treede RD, Magerl W
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(2011) Modality-specific somatosensory changes in a human surrogate model of postoperative pain. Anesthesiology 115: 387-397
Fißmer I, Klein T, Magerl W, Treede RD, Zahn PK, Pogatzki-Zahn EM
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(2012) Experimental characterization of the effects of acute stresslike doses of hydrocortisone in human neurogenic hyperalgesia models. Pain 153: 420-428
Michaux GP, Magerl W, Anton F, Treede RD
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(2013) Induction of the perceptual correlate of human long-term potentiation (LTP) is associated with the 5-HTT genotype. Brain Res. 491: 54-59
Matre D, Olsen MB, Jacobsen LM, Klein T, Gjerstad J
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(2013) Pinprick-evoked brain potentials: a novel tool to assess central sensitization of nociceptive pathways in humans. J Neurophysiol. 110: 1107-1116
Iannetti GD, Baumgärtner U, Tracey I, Treede RD, Magerl W
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(2014) An improved model of heat-induced hyperalgesia - repetitive phasic heat pain causing primary hyperalgesia to heat and secondary hyperalgesia to light touch and pinprick. PLoS ONE 9(6): e99507
Jürgens T, Sawatzki A, Henrich F, Magerl W, May A
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(2015) Capsaicin-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans. Brain 138:2505-2520
Henrich F, Magerl W, Klein T, Greffrath W, Treede RD
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(2015) Characterizing pinprick-evoked brain potentials before and after experimentally induced secondary hyperalgesia. J Neurophysiol. 114: 2672-2681
van den Broeke EN, Mouraux A, Groneberg AH, Pfau DB, Treede RD, Klein T
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(2016) High-frequency modulation of rat spinal field potentials: effects of slowly conducting muscle vs. skin afferents. J Neurophysiol. 115:692-700
Zhang J, Hoheisel U, Klein T, Magerl W, Mense S, Treede RD
