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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.

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Researchers involved



No evidence for an effect of selective spatial attention on the development of secondary hyperalgesia: a replication study

Front Hum Neurosci

Della Porta D, Vila ML, Kuzminova A, Filbrich L, Mouraux A, Legrain V.

in press.



Chronic temporomandibular disorders are associated with higher susceptibility to developing central sensitization: a case-control study


Cayrol T, van den Broeke EN, Gerard E, Meeus M, Mouraux A, Roussel N, Pitance L.

in press.


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

Clin Neurophysiol

Leone C, Di Lionardo A, Di Pietro G, Di Stefano G, Falco P, Blockeel AJ, Caspani O, Garcia-Larrea L, Mouraux A, Phillips KG, Treede RD, Truini A.



High-frequency electrical stimulation of cutaneous nociceptors differentially affects pain perception elicited by homotopic and heterotopic electrical stimuli

J Neurophysiol

van den Broeke EN, Urdi M, Mouraux A, Biurrun Manresa J, Torta DM



Human surrogate models of central sensitization: a critical review and practical guide

European Journal of Pain

Quesada C, Kostenko A, Ho I, Leone C, Nochi Z, Stouffs A, Wittayer M, Caspani O, Finnerup NB, Mouraux A, Pickering G, Tracey I, Truini A, Treede RD, Garcia-Larrea L.



Perceptual correlates of homosynaptic long term potentiation in human nociceptive pathways: a replication study

Royal Society Open Science

van den Broeke EN, Vanmaele T, Mouraux A, Stouffs A, Biurrun-Manresa J, Torta DM



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

European Journal of Pain

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



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

Journal of Neurophysiology

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 .



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

Journal of Neurophysiology

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



Central sensitization in humans: Popular phrase or useful concept?

Journal of Psychosomatic Research

van den Broeke EN, Van den Bergh O.



Central sensitization increases the pupil dilation elicited by mechanical pinprick stimulation

Journal of Neurophysiology

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


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