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 ϫ 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for Ͼ3 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 m 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 Ͼ3 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.

Analgesia to pressure–pain develops in the ipsilateral forehead after high- and low-frequency electrical stimulation of the forearm

“…In addition, electricallyevoked pain decreased over the course of LFS (Klein et al 2004;Rottmann et al 2008), consistent with activation of central inhibitory pain control mechanisms (Jung et al 2012;Rottmann et al 2010) and/or long-term depression in central pain processing pathways (Klein et al 2004). Thus, local and spinal responses to electrical stimulation differed markedly between the HFS and LFS conditions.…”

“…Furthermore, pain rose during HFS but decreased gradually during LFS conditioning, possibly due to habituation or the development of long term depression in spinal nociceptive pathways (Biurrun Manresa et al 2010;Klein et al 2004;Rankin et al 2009;Rottmann et al 2008). Despite these differences, decreases in sensitivity to pressurepain in the forehead were similar after both forms of electrical stimulation, suggesting that HFS and LFS triggered similar pain inhibitory processes.…”

“…In contrast to HFS, LFS induces a long-lasting decrease in synaptic strength in spinal nociceptive pathways, resulting in hypoalgesia at the site of stimulation (Aymanns et al 2009;Jung et al 2011;Rottmann et al 2008); in addition, LFS evokes only minor signs of secondary hyperalgesia in adjacent skin (Klein et al 2004). Together, these findings suggest that LFS triggers stronger inhibitory processes than HFS.…”

Heterosynaptic Long-Term Potentiation at GABAergic Synapses of Spinal Lamina I Neurons

“…Long-term potentiation (LTP) at glutamatergic synapses between nociceptive nerve fibers and spinal dorsal horn neurons has been studied intensively (Randic et al, 1993;Ikeda et al, 2003Ikeda et al, , 2006Drdla et al, 2009). Perceptual correlates of LTP in nociceptive pathways have been demonstrated in humans (Klein et al, 2004), and behavioral correlates exist in animals (Zhang et al, 2005). In striking contrast, nothing is presently known about long-term changes of synaptic efficacy at spinal inhibitory synapses.…”

Involvement of Opioid Receptors and α2-Adrenoceptors in Inhibitory Pain Modulation Processes: A Double-Blind Placebo-Controlled Crossover Study

“…This was considered to be the minimum number required to test the study hypotheses, based on previous studies of HFS. 19,20,25,46,[48][49][50][51] Recruitment began in February 2014 and data collection finished in July 2015.…”