Long‐term facilitation of nociceptive withdrawal reflexes following low‐frequency conditioning electrical stimulation: A new model for central sensitization in humans

Abstract

Central sensitization is believed to be one of the key mechanisms behind chronic pain conditions, and several models have been developed in order to characterize this phenomenon in humans. One of these models relies on conditioning electrical stimulation to elicit long-lasting effects on the nociceptive system. The aim of this study was to evaluate these effects using an objective electrophysiological measurement, the nociceptive withdrawal reflex (NWR). Long-term changes in spinal nociception after high- and low-frequency conditioning electrical stimulation were assessed in 13 healthy volunteers. Perceptual intensity ratings to mechanical stimuli and blood flow variations were assessed in the conditioned area (dorsum of the foot) and surroundings. To evaluate the excitability of the nociceptive system, the NWR was elicited within the same innervation area (superficial peroneal nerve) at graded stimulation intensities and recorded in the hamstrings. Following low-frequency stimulation, an intensity-independent long-lasting facilitation of the NWR was observed, with a significant increase in the reflex size (average of 31+/-4%, p<0.001) and in the number of reflexes (average increase of 22+/-10%, p<0.01), accompanied by a significant increase in the blood flow (average increase of 40+/-10%, p<0.001). These findings suggest that activity-dependent central sensitization can be elicited using conditioning electrical stimulation with a stimulation frequency that lies within the physiological firing range of primary afferents, and that it can be objectively assessed in humans using the NWR.

How different experimental models of secondary hyperalgesia change the nociceptive flexion reflex

“…Previous studies have reported conflicting evidence on how HFS-and capsaicin-induced central sensitization influence RIII reflex size (Andersen et al, 1995;Andersen et al, 1996;Manresa et al, 2010). While some studies have reported that central sensitization alone does not increase RIII reflex size (Andersen et al, 1995;Andersen et al, 1996;), others have shown that central sensitization induced by continuous low-frequency stimulation (Manresa et al, 2010) or concomitant thermal stimulation (Andersen et al, 1995) increases RIII reflex size, thus indicating that the modulation of this variable likely requires ongoing somatosensory afferent summation to the dorsal horn. Accordingly, we did not find any RIII reflex size modulation probably because HFS and topical capsaicin elicited short-term painful sensations and did not trigger ongoing afferent summation.…”

“…Several studies showed that the RIII reflex threshold is reduced during capsaicin-induced central sensitization (Grönroos and Pertovaara, 1993;Andersen et al, 1995), as well as in patients with chronic pain (García-Larrea and François, 1990;Leroux et al, 1995;Desmeules et al, 2003;Banic et al, 2004;Coffin et al, 2004). However, it is still unclear whether reflex size is similarly affected by central sensitization (Andersen et al, 1995;Andersen et al, 1996;Arendt-Nielsen et al, 1994;Manresa et al, 2010). Moreover, noxious conditioning stimuli capable of inducing central sensitization may also trigger endogenous pain modulatory systems.…”

Test-Retest Reliability of 10 Hz Conditioning Electrical Stimulation Inducing Long-Term Potentiation (LTP)-Like Pain Amplification in Humans

“…The assessments consisted of neurogenic inflammation imaging using laser speckle blood-flow imagery for measuring superficial blood flow (SBF) and infrared thermography for measuring skin temperature (ST), assessments of pinprick and light-stroking perception intensities surrounding the conditioned site (heterotopic), perceived intensity to homotopic single electrical stimulation (SES) and heat pain threshold (HPT) at the conditioned site. To evaluate perceived stimulation intensity, a VAS was used that was anchored from 0 (no sensation) to 100 (the most intense pain imaginable) where 30 indicated the pain threshold [ 28 , 30 – 32 ]. The same researcher performed all experiments to rule out the inter-rater variation.…”

Exploration of the conditioning electrical stimulation frequencies for induction of long-term potentiation-like pain amplification in humans

“…The stimulations were applied with an epicutaneous pin electrode (EPE) consisting of a circular array (diameter: 10 mm) of fifteen cathodal electrodes each with diameter of 0.2 mm, protruding 1 mm from the base, and a large circular stainless steel plate served as an anode with an inner diameter of 20 mm and an outer diameter of 40 mm placed concentrically around the cathodes (Fig. 1A) (Biurrun Manresa et al, 2010). This electrode has been verified to induce a sensation of pain at a lower stimulation intensity compared with conventional cutaneous nerve stimulation because the diameter of the cathodes is smaller so a high current density is achieved in the epidermal layers where the nociceptive Aδ-and C fibers terminate (Kaube et al, 2000;Katsarava et al, 2006;Mouraux et al, 2010;Mørch et al, 2011).…”