Maile Laura, Mercado Krista, Baig Leena, Davidson Steve
Neuroscience Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
J Pain. 2025 Aug;33:105452. doi: 10.1016/j.jpain.2025.105452. Epub 2025 May 29.
Chronic stress and chronic pain exacerbate one another and worsen outcomes in clinical populations. The anatomical locations where neurophysiological changes underlying chronic stress and pain comorbidity could occur are poorly explored. In this study, we implemented a mouse model of chronic unpredictable stress (CUS) to test the effects of established stress on reflexive and nonreflexive pain behaviors and the ability to recover from painful neuropathy and post-operational injury. We further examined the effects of stress on neuronal structure and function in a subregion of the medial prefrontal cortex, the prelimbic cortex (PL), an area implicated in both stress and pain. CUS induced thermal hypersensitivity, mechanical allodynia, and reduced pain tolerance in male, but not in female, mice. Stressed male mice also showed persistent hypersensitivity and anxiety-like behavior compared to controls following chemotherapy and paw incision injuries. cFos expression in PL following an acute noxious stimulus was reduced in CUS mice indicating reduced prefrontal activity. However, PL layer V neurons that project to the ventrolateral periaqueductal gray (vlPAG) did not show changes in density of dendritic spines in distal branches of the apical dendrite, nor did they show changes in intrinsic membrane excitability following CUS. In contrast, CUS did produce increased spontaneous inhibitory drive onto PL-vlPAG neurons, altering the excitatory to inhibitory ratio. Our results suggest that stress and pain work in conjunction to promote persistent hypersensitivity and negative affective behaviors, and provide evidence that stress increases inhibitory synaptic transmission onto mPFC-vlPAG descending projection neurons. Perspective: Chronic unpredictable stress produced hypersensitivity and worsened outcomes after a painful injury in male mice. The prelimbic cortex is identified as an important region where chronic stress may modulate pain. We demonstrate a clinically relevant model that can be used to investigate neural correlates underlying stress and pain interactions.
慢性应激和慢性疼痛会相互加剧，并使临床患者的病情恶化。目前，对于慢性应激和疼痛共病背后神经生理变化可能发生的解剖学位置，人们了解甚少。在本研究中，我们实施了一种慢性不可预测应激（CUS）小鼠模型，以测试既定应激对反射性和非反射性疼痛行为的影响，以及从疼痛性神经病变和术后损伤中恢复的能力。我们进一步研究了应激对内侧前额叶皮质的一个亚区域——前边缘皮质（PL）的神经元结构和功能的影响，该区域与应激和疼痛均有关联。CUS诱导了雄性小鼠而非雌性小鼠的热超敏反应、机械性异常性疼痛，并降低了疼痛耐受性。与对照组相比，应激雄性小鼠在化疗和爪部切开损伤后还表现出持续的超敏反应和焦虑样行为。急性有害刺激后，CUS小鼠PL中的cFos表达降低，表明前额叶活动减少。然而，投射到腹外侧导水管周围灰质（vlPAG）的PL第V层神经元，其顶端树突远端分支的树突棘密度没有变化，CUS后其内在膜兴奋性也没有变化。相反，CUS确实增加了对PL-vlPAG神经元的自发性抑制驱动，改变了兴奋与抑制的比例。我们的结果表明，应激和疼痛共同作用促进了持续的超敏反应和负面情感行为，并提供证据表明应激增加了对内侧前额叶皮质-腹外侧导水管周围灰质下行投射神经元的抑制性突触传递。观点：慢性不可预测应激导致雄性小鼠在疼痛性损伤后出现超敏反应并使病情恶化。前边缘皮质被确定为慢性应激可能调节疼痛的重要区域。我们展示了一个与临床相关的模型，可用于研究应激和疼痛相互作用背后的神经关联。
