Central sensitization and secondary hyperalgesia

Patients with neuropathic pain do not only show negative symptoms (i.e. a sensory deficit) related to the impairment of somatosensory pathways. Instead, they also show, paradoxical positive symptoms (ongoing pain, hyperalgesia and allodynia), indicating an increased responsiveness of nociceptive pathways. A prominent positive sign of neuropathic pain is increased sensitivity to noxious mechanical stimulation (mechanical or pinprick hyperalgesia). At present, there is no reliable and objective laboratory toolto assess these changes in the neural responsiveness to mechanonociceptive input. The mechanisms underlying these positive symptoms are different from those underlying the negative symptoms, and involve activity-dependent changes in both the peripheral and the central nervous system. Some patients can have a severe impairment without positive symptoms, while other patients can have a mild impairment but severe positive symptoms.

The mechanical hyperalgesia observed in patients with neuropathic pain is very similar to the mechanical hyperalgesia that can be induced by the sustained activation of nociceptors in healthy volunteers ("secondary hyperalgesia"). There is convincing evidence that mechanical hyperalgesia results from a facilitation of nociceptive transmission at the level of the spinal cord, i.e. central sensitization.

In an attempt to develop a biomarker for central sensitization, we recently conducted a study in which we recorded pinprick evoked brain potentials (PEPs) in the area of experimentally induced secondary mechanical hyperalgesia in healthy volunteers. We showed that when pinprick stimuli are applied in the area of secondary mechanical hyperalgesia, PEPs were significantly increased as compared to the responses elicited by stimulation of normal skin. Moreover, in a second study, we showed that this enhancement of PEPs is long lasting and follows the same time course as the mechanical hyperalgesia. These promising results suggest that the recording of PEPs could be used as a diagnostic tool to assess the positive symptoms of neuropathic pain.

Researchers involved


European Journal of Pain

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


Cayrol T, Lebleu J, Mouraux A, Roussel N, Pitance L, van den Broeke E.

in press

Journal of Neurophysiology

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


Gousset S, Mouraux A, van den Broeke EN.



The focus of spatial attention during the induction of central sensitization can modulate the subsequent development of secondary hyperalgesia


Filbrich L, van den Broeke E, Legrain V, Mouraux .


Journal of Neurophysiology

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


van den Broeke EN, Gousset S, Bouvy J, Stouffs A, Lebrun L, van Neerven SGA, Mouraux A.


Journal of Psychosomatic Research

Central sensitization in humans: Popular phrase or useful concept?


van den Broeke EN, Van den Bergh O.


Journal of Neurophysiology

Central sensitization increases the pupil dilation elicited by mechanical pinprick stimulation


van den Broeke EN, Hartgerink DM, Butler J, Lambert J, Mouraux A.


Pain Reports

No evidence of widespread mechanical pressure hyperalgesia after experimentally-induced central sensitization via skin nociceptors


Cayrol T, Pitance L, Roussel N, Mouraux A, van den Broeke EN.

3(6): e691

F1000 Research

Central sensitization and pain hypersensitivity: some critical considerations


van den Broeke EN.

PLoS One

High frequency electrical stimulation induces a long-lasting enhancement of event-related potentials but does not change the perception elicited by intra-epidermal electrical stimuli delivered to the area of increased mechanical pinprick sensitivity


Manresa JB, Andersen OK, Mouraux A, van den Broeke EN.


Journal of Physiology

Quickly-responding C-fiber nociceptors contribute to heat hypersensitivity in the area of secondary hyperalgesia


Lenoir C, Plaghki L, Mouraux A, van den Broeke EN.

in press

Clinical Psychological Science

Central sensitization: explanation or phenomenon?


van den Broeke EN, Torta DM, Van den Bergh O.

in press

Nature: Scientific Reports

No perceptual prioritization of non-nociceptive vibrotactile and visual stimuli presented on a sensitized body part


Torta D, Filbrich L, van den Broeke E, Legrain V.


Institute of Neuroscience (IONS) - Université catholique de Louvain (UCL)