Heterosynaptic facilitation of mechanical nociceptive input is dependent on the frequency of conditioning stimulation

Abstract

High-frequency burstlike electrical conditioning stimulation (HFS) applied to human skin induces an increase in mechanical pinprick sensitivity of the surrounding unconditioned skin (a phenomenon known as secondary hyperalgesia). The present study assessed the effect of frequency of conditioning stimulation on the development of this increased pinprick sensitivity in humans. In a first experiment, we compared the increase in pinprick sensitivity induced by HFS, using monophasic non-charge-compensated pulses and biphasic charge-compensated pulses. High-frequency stimulation, traditionally delivered with non-charge-compensated square-wave pulses, may induce a cumulative depolarization of primary afferents and/or changes in pH at the electrode-tissue interface due to the accumulation of a net residue charge after each pulse. Both could contribute to the development of the increased pinprick sensitivity in a frequency-dependent fashion. We found no significant difference in the increase in pinprick sensitivity between HFS delivered with charge-compensated and non-charge-compensated pulses, indicating that the possible contribution of charge accumulation when non-charge-compensated pulses are used is negligible. In a second experiment, we assessed the effect of different frequencies of conditioning stimulation (5, 20, 42, and 100 Hz) using charge-compensated pulses on the development of increased pinprick sensitivity. The maximal increase in pinprick sensitivity was observed at intermediate frequencies of stimulation (20 and 42 Hz). It is hypothesized that the stronger increase in pinprick sensitivity at intermediate frequencies may be related to the stronger release of substance P and/or neurokinin-1 receptor activation expressed at lamina I neurons after C-fiber stimulation. NEW & NOTEWORTHY Burstlike electrical conditioning stimulation applied to human skin induces an increase in pinprick sensitivity in the surrounding unconditioned skin (a phenomenon referred to as secondary hyperalgesia). Here we show that the development of the increase in pinprick sensitivity is dependent on the frequency of the burstlike electrical conditioning stimulation.

The influence of a manipulation of threat on experimentally-induced secondary hyperalgesia

“…It was plausible that the individual calibration approach could have confounded the results because the current for the HFS was linked to the individual detection threshold, and HFS delivered at a higher current could result in greater secondary hyperalgesia. Although previous published datasets ( Torta et al, 2017 ; van den Broeke et al, 2017 ; van den Broeke et al, 2019 ; van den Broeke et al, 2019 ; Van den Broeke et al, 2016 ; van den Broeke, Lenoir & Mouraux, 2016 ) ( n = 170, unpublished) investigation found no association between the individual electrical detection threshold and the magnitude of secondary hyperalgesia. We checked this by testing for a correlation between the individually determined electrical detection threshold and magnitude of secondary hyperalgesia in our data.…”

Burst-like conditioning electrical stimulation is more efficacious than continuous stimulation for inducing secondary hyperalgesia in humans

“…The total duration of their conditioning stimulation was around 16 min, and the stimulation was applied to the ventral forearm. Also Torta et al (2019) showed an increase in pinprick sensitivity of the skin after 2 min of 2-Hz continuous stimulation at the forearm.…”

“…In experiment 2, 40 healthy volunteers were included (5-Hz burst-like stimulation: n ϭ 20, 7 men and 13 women; age 18 -40 yr, 23.0 Ϯ 4.9 yr; 5-Hz continuous stimulation: n ϭ 20, 7 men and 13 women; age 19 -27 yr, 22.6 Ϯ 2.3 yr). Parts of the data were reused from the 5-Hz continuous stimulation condition of experiment 1 (n ϭ 15) and the 5-Hz burst-like stimulation condition of our previously collected data set (n ϭ 15; van den Broeke et al 2019). Comparison of these two groups of 15 participants did not reach statistical significance.…”

“…To assess changes in pinprick sensitivity, we followed the same method as described in our previous study (van den Broeke et al 2019), which is summarized here. A calibrated pinprick stimulator exerting a normal force of 128 mN with the use of a 0.25-mm probe (MRC Systems, Heidelberg, Germany) was applied perpendicular to the skin.…”

Within‐ and between‐session reliability of secondary hyperalgesia induced by electrical high‐frequency stimulation

“…In addition, capsaicin or heat typically induces after-sensations, which is not the case for electrical stimulation. Furthermore, parameters such as the pattern and frequency of electrical stimulation can be easily controlled, which has recently led to the finding that burst-like 42 Hz stimulation seem the optimal parameters for inducing SH (Van Den Broeke et al, 2019;Gousset et al, 2019).…”