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Nucleus accumbens mediates the pronociceptive effect of sleep deprivation

the role of adenosine A2A and dopamine D2 receptors

Sardi, Natalia Fantin; Tobaldini, Glaucia; Morais, Rosana Nogueira; Fischer, Luana*

doi: 10.1097/j.pain.0000000000001066
Research Paper
Editor's Choice

Sleep disorders increase pain sensitivity and the risk of developing painful conditions; however, the underlying mechanisms are poorly understood. It has been suggested that nucleus accumbens (NAc) influences sleep-wake cycle by means of a balance between adenosine activity at A2A receptors and dopamine activity at D2 receptors. Because the NAc also plays an important role in pain modulation, we hypothesized that the NAc and its A2A and D2 receptors mediate the pronociceptive effect of rapid eye movement (REM) sleep deprivation (SD). We found that 24 hours of REM-SD induced an intense pronociceptive effect in Wistar rats, which decreases progressively over a sleep rebound period. Although the level of fecal glucocorticoid metabolites increased with SD within group, it did not differ between sleep-deprived group and control group, indicating a stress response with similar magnitude between groups. The pronociceptive effect of REM-SD was prevented by excitotoxic lesion (N-Methyl-D-aspartate, 5.5 μg) of NAc and reverted by its acute blockade (Qx-314, 2%). The administration of an A2A receptor antagonist (SCH-58261, 7 ng) or a D2 receptor agonist (piribedil, 6 μg) into the NAc increased home cage activity and blocked the pronociceptive effect of REM-SD. Complementarily, an A2A receptor agonist (CGS-21680, 24 ng) impaired the reversal of the pronociceptive effect and decreased home cage activity, as it did a D2 receptor antagonist (raclopride, 5 μg). Rapid eye movement SD did not affect the expression of c-Fos protein in NAc. These data suggest that SD increases pain by increasing NAc adenosinergic A2A activity and by decreasing NAc dopaminergic D2 activity.

Sleep deprivation increases pain by a nucleus accumbens–dependent mechanism based on increased adenosinergic A2A activity and decreased dopaminergic D2 activity.

Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, Brazil

Corresponding author. Address: Luana Fischer, Department of Physiology, Division of Biological Sciences, Federal University of Parana, Curitiba, Parana, 81531-990, Brazil. Tel.: +55 41 3361-1738. E-mail address: (L. Fischer).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

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Received March 10, 2017

Received in revised form August 24, 2017

Accepted August 28, 2017

© 2018 International Association for the Study of Pain
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