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1. Pain 140 (2008) 393–394
www.elsevier.com/locate/pain
Letter to the Editor
Habituation to painful stimulation involves the We can now complement this finding by presenting
antinociceptive system - a 1-year follow-up of 10 participants the 1-year follow-up data of this study: 12 months after
the initial study, we were able to recruit 10 of the initial
Repetitive painful stimulation can lead to substantial participants (n = 16) to undergo a single and identical
attenuation of pain-related responses. This phenomenon pain-stimulation session in the MRI scanner and to
is clinically highly relevant as it may represent an impor- show that the pain thresholds normalized to baseline
tant protection strategy to the development of chronic (see Fig. 1A). The pain ratings to identical thermal
pain states. However, detailed information regarding stimuli displayed a similar behaviour: a significant de-
the underlying mechanisms and its temporal dynamics crease in pain ratings was observed from day 1 to days
is only just being elucidated. 8 and 22 (p < 0.05, paired T-Test.) However, by the 1-
In a recent study published in this journal [3], we used year follow-up no difference was found when compared
fMRI to investigate adaptive changes in the central ner- with the initial pain ratings (VAS-ratings [0–100] were
vous system to the repetitive application of a 20-minute 76.7, 60.8, 59.2 and 70.9 for days 1, 8, 22 and at 1
thermal pain paradigm over eight consecutive days. This year).
procedure resulted in substantially decreased pain rat- Remarkably, the same response pattern (change in
ings to identical painful stimuli. Comparison of brain- BOLD over time which receded after 12 months) was
related responses on days 1 and 8 showed that the re- observed in the rACC, which we previously reported
duced pain perception over time was reflected in de- to be associated with the habituation to pain over 1
creased BOLD responses to nociceptive stimuli in week. The rACC activation [9, 30, À12, for x, y, z in
classical pain areas (e.g. the thalamus, insula, SII and MNI coordinates] with respective parameter estimates
the putamen). Most importantly, we found that the over the time course is illustrated in Fig. 1B/C.
habituation to pain over the 8-day period is associated Taken together these findings substantiate the con-
with an increased activity in the subgenual area of the cept, that the habituation to painful stimuli is an active
rACC. Given this area’s established role in the endoge- process that engages an increased activity of the endog-
nous modulation of pain [1,2,4], this finding strongly enous antinociceptive system. This mechanism repre-
suggests that the habituation to pain is in part mediated sents a temporally adaptive process that outlasts the
by increased activity of the central antinociceptive sys- period of intensive/repetitive painful stimulation (as
tem. In our previous paper the pain paradigm in combi- can be seen on day 22), but recedes when the recurrent
nation with fMRI was repeated 2 weeks after the nociceptive input terminates. Admittedly, our follow-
experimental phase. Although no further nociceptive up investigation after 12 months only allows for a
stimulus was given, none of the observed behavioural rough assessment of the temporal dynamics of the
(pain thresholds, rating) or biological measures (fMRI) long-term habituation to pain. Future studies are
of habituation displayed a significant change between necessary to further investigate its temporal character-
days 8 and 22. This finding indicated that the functional istics and most importantly to evaluate how pharmaco-
adaptive changes induced by the 1 week painful stimula- logical or contextual manipulations can impact this
tion outlasted this time-frame. mechanism.
0304-3959/$34.00 Ó 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2008.09.030

2. 394 Letter to the Editor / Pain 140 (2008) 393–394
A 49
* *
Pain Threshold C°
48
47
B
46
45
44
day 1 day 8 day 22 1 year
C
0.2
Parameter Estimates
0
rACC
0.2
day 1 day 8 day 22 1 year
Fig. 1. Behavioural results (A) Pain thresholds for the stimulated hand over the course of the experiment. Note the increase of pain thresholds from
day 1 to days 8 and 22 and the decrease from day 22 to 1 year. Significant differences (p < 0.05) are marked by an asterisk. Neuroimaging results
(B/C) Time-dependent changes in pain-related activity overlaid on a structural T1-weighted MRI used for spatial normalization. (B) We tested for a
region that showed an increase of activity with behavioural habituation, which showed the reverse behaviour after 1 year. The rACC, specifically the
subgenual area of the rACC, displays a reversible increase of activity with behavioural habituation, Z = 3.3, p < 0.001. Respective parameter
estimates are shown in 1C. Error bars indicate the 95% confidence interval of the group mean.
Acknowledgements [3] Bingel U, Schoell E, Herken W, Buchel C, May A. Habituation to
painful stimulation involves the antinociceptive system. Pain
2007;131:21–30.
A. May was supported by a grant of the Deutsche [4] Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid
Forschungsgemeinschaft (MA 1862/2). U. Bingel was analgesia–imaging a shared neuronal network. Science 2002;295:
supported by local university funding (FFM). This 1737–40.
study was supported by a grant of the Federal Ministry
of Education and Research (BMBF project no. 371 57 U. Bingel *
01 & NeuroImageNord). W. Herken
Department of Neurology,
University of Hamburg (UKE),
References Martinistr. 52, D-20246 Hamburg,
Germany
[1] Bantick SJ, Wise RG, Ploghaus A, Clare S, Smith SM, Tracey I. E-mail address: bingel@uke.uni-hamburg.de (U. Bingel)
Imaging how attention modulates pain in humans using functional
MRI. Brain 2002;125:310–9. S. Teutsch
[2] Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C. Mechanisms of A. May
placebo analgesia: rACC recruitment of a subcortical antinocicep-
NeuroImage Nord,
tive network. Pain 2006;120:8–15.
Department of Systems Neuroscience,
University of Hamburg (UKE), Germany
*
Corresponding author. Tel.: +49 40 42803 9962; fax: +49 40 42803
9955.