High-frequency electrical stimulation (HFS) of skin nociceptors triggers central sensitization (CS), manifested as increased pinprick sensitivity of the skin surrounding the site of HFS. Our aim was to assess the effect of CS on pinprick-evoked pupil dilation responses (PDRs) and pinprick-evoked brain potentials (PEPs). We hypothesized that the increase in the positive wave of PEPs following HFS would result from an enhanced pinprick-evoked phasic response of the locus coeruleus-noradrenergic

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... stem (LC-NS), indicated by enhanced PDRs. In 14 healthy volunteers, 64- and 96-mN pinprick stimuli were delivered to the left and right forearms, before and 20 minutes after HFS was applied to one of the two forearms. Both PEPs and pinprick-evoked PDRs were recorded. After HFS, pinprick stimuli were perceived as more intense at the HFS-treated arm compared with baseline and control site, and this increase was similar for both stimulation intensities. Importantly, the pinprick-evoked PDR was also increased, and the increase was stronger for 64- compared with 96-mN stimulation. This is in line with our previous results showing a stronger increase of the PEP positivity at 64 vs. 96-mN stimulation and suggests that the increase in PEP positivity observed in previous studies could relate, at least in part, to enhanced LC-NS activity. However, there was no increase of the PEP positivity in the present study, indicating that enhanced LC-NS activity is not the only determinant of the HFS-induced enhancement of PEPs. Altogether, our results indicate that PDRs are more sensitive for detecting CS than PEPs. NEW & NOTEWORTHY We provide the first demonstration in humans that activity-dependent central sensitization increases pinprick-evoked autonomic arousal measured by enhanced pupil dilation response.