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.

Figures

Figure 1.

Experimental procedure for testing the roles of LTP and LTD in human pain perception. A, Conditioning electrical HFS or LFS was applied to the proximal volar forearm via a circular array of electrodes. Homotopic effects of HFS and LFS on the conditioned pathway were tested by pain ratings to single pulses through the conditioning electrode. Heterotopic effects outside of the conditioned pathway were tested by pain ratings to mechanical stimuli at a distance of 15 mm from the electrode arrays. B, Testing of mechanical sensitivity consisted of stimulus–response functions for pricking pain with punctate probes and soft stroking. Testing was arranged in runs comprising all 10 mechanical stimuli in a randomized order (small black bars) followed by three electrical pulses at 10× the detection threshold (•) with 5–10 sec interstimulus intervals. Runs were alternated between the conditioned skin site and the control site for 40 min before and 60 min after HFS or LFS. At the end of the experiment, the area of hyperalgesia to mechanical stimuli was mapped using a 200 mN von Frey hair. C, Laser Doppler imaging revealed large areas of increased skin perfusion (flare) at sites of HFS and LFS (20 × T).

Figure 2.

Pain sensations evoked by conditioning electrical stimuli. A, HFS (5× 1 sec at 100 Hz; 10 sec intervals between bursts) elicited pain sensations that increased over the five bursts. B, During LFS (1000 pulses at 1 Hz), pain ratings increased over the first 150 pulses and then slowly declined until the end of the conditioning stimulation, when pain ratings were lower than the initial values. Mean ± SEM values across eight subjects are shown. Each filled triangle or filled square represents average pain ratings on a 100 point verbal rating scale. ▴, 10 × T; ▪, 20 × T.

Figure 3.

Homotopic effects of conditioning electrical stimuli. A, After LFS, pain evoked by single electrical test pulses (intensity, 10 × T) through the HFS electrode increased to ∼30% above baseline (•). This facilitation lasted until the end of the observation period. Pain evoked by identical test pulses through a remote electrode exhibited a small decrease over time (○). B, After LFS, pain evoked by single electrical test pulses through the LFS electrode decreased to ∼30% below baseline (•). This inhibition was not reversible within the observation period. Mean ± SEM values across seven subjects are shown. Dotted lines indicate mean level of baseline period. Each circle represents normalized pain ratings averaged over a 5 min time window across stimulation intensities (10 × T; 20 × T). Asterisks indicate post hoc paired t tests; conditioned versus control site; p < 0.05.

Figure 4.

Heterotopic effects of conditioning electrical stimuli on pin prick-evoked pain. A, B, Conditioning HFS induced a significant enhancement of pin prick-evoked pain adjacent to the conditioning electrode (•) but not adjacent to the control electrode (○). This secondary hyperalgesia occurred after conditioning stimulus intensities of 10 × T and 20 × T. Pain perception was significantly increased already at 5 min and remained potentiated throughout the 60 min observation period (10 × T) or even increased further (20 × T). C, Conditioning LFS at 10 × T induced no changes in pin prick-evoked pain at any test site. D, For conditioning LFS at 20 × T, a small but significant increase in pin prick-evoked pain was found near the conditioning electrode but not the control electrode. Mean ± SEM values across eight subjects are shown. Dotted lines indicate mean level of baseline period. Each circle represents the normalized average of pain ratings across all seven stimulus intensities over a 5 min time window. Asterisks indicate post hoc paired t tests; conditioned versus control site; p < 0.05.

Figure 5.

Heterotopic effects of conditioning electrical stimuli on touch-evoked pain. A, B, Conditioning HFS induced a state in which these tactile, normally non-noxious stimuli became painful adjacent to the conditioning electrode (•) (allodynia) but not adjacent to the control electrode (○). Allodynia gradually developed after HFS and persisted throughout the 60 min observation period. C, Conditioning LFS at 10 × T elicited no allodynia. D, For conditioning LFS at 20 × T, one subject developed allodynia near the conditioning electrode but not the control electrode. Mean ± SEM values across eight subjects are shown. Each circle represents the normalized average of pain ratings across all three stimulus intensities over a 5 min time window. Asterisks indicate post hoc paired t tests; conditioned versus control site; p < 0.05.

Figure 6.

Stimulus–response functions for punctate probes and light tactile stimuli after HFS at 20 × T. A, Allodynia. Light tactile stimuli were not painful when moved across normal skin before conditioning stimulation (○). Adjacent to the conditioning electrode, the same stimuli were mildly painful after HFS at 20 × T (•). CW, 3 mN; QT, 100 mN; BR, 400 mN. B, Secondary hyperalgesia. The stimulus–response function for punctate probes was approximately linear in log–log coordinates in normal skin (○). After HFS, there was a parallel leftward shift of this function adjacent to the conditioning electrode (•). C, D, There was neither allodynia nor hyperalgesia adjacent to the unstimulated control site. Mean ± SEM values across eight subjects are shown. Each circle represents average pain ratings on a 100 point verbal rating scale. Asterisks indicate post hoc paired t tests; preconditioning versus postconditioning stimulation; p < 0.05.