Abstract：
Sleep disturbances and persistent pain conditions are public health challenges worldwide. Although it is well-known that sleep deficit increases pain sensitivity, the underlying mechanisms remain elusive. We have recently demonstrated the involvement of nucleus accumbens (NAc) and anterior cingulate cortex (ACC) in the pronociceptive effect of sleep restriction. In this study, we found that sleep restriction increases c-Fos expression in NAc and ACC, suggesting hyperactivation of these regions during prolonged wakefulness in male Wistar rats. Blocking adenosine A2A receptors in the NAc or GABAA receptors in the ventral tegmental area (VTA), dorsal raphe nucleus (DRN), or locus coeruleus (LC) effectively mitigated the pronociceptive effect of sleep restriction. In contrast, the blockade of GABAA receptors in each of these nuclei only transiently reduced carrageenan-induced hyperalgesia. Pharmacological activation of dopamine D2, serotonin 5-HT1A and noradrenaline alpha-2 receptors within the ACC also prevented the pronociceptive effect of sleep restriction. While pharmacological inhibition of these same monoaminergic receptors in the ACC restored the pronociceptive effect which had been prevented by the GABAergic disinhibition of the of the VTA, DRN or LC. Overall, these findings suggest that the pronociceptive effect of sleep restriction relies on increased adenosinergic activity on NAc, heightened GABAergic activity in VTA, DRN, and LC, and reduced inhibitory monoaminergic activity on ACC. These findings advance our understanding of the interplay between sleep and pain, shedding light on potential NAc-brainstem-ACC mechanisms that could mediate increased pain sensitivity under conditions of sleep impairment.
摘要：
睡眠障碍和持续性疼痛是全球公共卫生挑战。尽管众所周知睡眠不足会增加疼痛敏感性，潜在的机制仍然难以捉摸。我们最近证明了伏隔核（NAc）和前扣带回皮质（ACC）参与了睡眠限制的先兆效应。在这项研究中,我们发现睡眠限制会增加NAc和ACC中的c-Fos表达，提示雄性Wistar大鼠在长时间清醒期间这些区域过度激活。在腹侧被盖区（VTA）的NAc或GABAA受体中阻断腺苷A2A受体，中缝背核(DRN),或蓝斑（LC）有效地减轻了睡眠限制的前兆效应。相比之下,这些核中每个核中GABAA受体的阻断仅暂时减少了角叉菜胶诱导的痛觉过敏。ACC内多巴胺D2，5-羟色胺5-HT1A和去甲肾上腺素α-2受体的药理激活也阻止了睡眠限制的先兆效应。虽然ACC中这些相同的单胺能受体的药理抑制作用恢复了由VTA的GABA能抑制所阻止的先兆效应，DRN或LC。总的来说,这些发现表明，睡眠限制的先兆效应依赖于增加的腺苷对NAc的活性，VTA中GABA能活性增强，DRN,LC,和降低对ACC的抑制单胺能活性。这些发现促进了我们对睡眠和疼痛之间相互作用的理解，阐明在睡眠障碍条件下可能介导疼痛敏感性增加的潜在NAc-脑干-ACC机制。
