title: Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans.
abstract: Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are ubiquitous mechanisms of synaptic plasticity, but their functional relevance in humans remains obscure. Here we report that a long-term increase in perceived pain to electrical test stimuli was induced by high-frequency electrical stimulation (HFS) (5 x 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for >3 hr). In contrast, a long-term decrease in perceived pain (27% below baseline, undiminished for 1 hr) was induced by low-frequency stimulation (LFS) (17 min at 1 Hz). Pain testing with punctate mechanical probes (200 microm diameter) in skin adjacent to the HFS-LFS conditioning skin site revealed a marked twofold to threefold increase in pain sensitivity (secondary hyperalgesia, undiminished for >3 hr) after HFS but also a moderate secondary hyperalgesia (30% above baseline) after strong LFS. Additionally, HFS but not LFS caused pain to light tactile stimuli in adjacent skin (allodynia). In summary, HFS and LFS stimulus protocols that induce LTP or LTD in spinal nociceptive pathways in animal experiments led to similar LTP- and LTD-like changes in human pain perception (long-term hyperalgesia or hypoalgesia) mediated by the conditioned pathway. Additionally, secondary hyperalgesia and allodynia in adjacent skin induced by the HFS protocol and, to a minor extent, also by the LFS protocol, suggested that these perceptual changes encompassed an LTP-like heterosynaptic facilitation of adjacent nociceptive pathways by a hitherto unknown mechanism.
authors.affiliation: Institute of Physiology and Pathophysiology, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.forename: Walter
authors.initials: W
authors.lastname: Magerl
authors.forename: Hanns-Christian
authors.initials: HC
authors.lastname: Hopf
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sandkühler
authors.forename: Rolf-Detlef
authors.initials: RD
authors.lastname: Treede
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D003213:Conditioning, Psychological / Q000502:physiology; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D005542:Forearm / Q000502:physiology; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods* / Q000706:statistics & numerical data; D017288:Pain Threshold / Q000502:physiology*; D012680:Sensitivity and Specificity; D012867:Skin / Q000294:innervation; D013116:Spinal Cord / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology