Nucleus accumbens mediates the pronociceptive effect of sleep deprivation: the role of adenosine A2A and dopamine D2 receptors

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 A(2A) receptors and dopamine activity at D-2 receptors. Because the NAc also plays an important role in pain modulation, we hypothesized that the NAc and its A(2A) and D-2 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 mu g) of NAc and reverted by its acute blockade (Qx-31 4, 2%). The administration of an A(2A) receptor antagonist (SCH-58261, 7 ng) or a D-2 receptor agonist (piribedil, 6 mu g) into the NAc increased home cage activity and blocked the pronociceptive effect of REM-SD. Complementarily, an A(2A) receptor agonist (CGS-21680, 24 ng) impaired the reversal of the pronociceptive effect and decreased home cage activity, as it did a D-2 receptor antagonist (raclopride, 5 mu g). 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 A(2A) activity and by decreasing NAc dopaminergic D-2 activity.