Fieldwalker Anna, Patel Ryan, Zhao Lucy, Kucharczyk Mateusz W, Mansfield Michael, Bannister Kirsty
Mroue Fateh Centre for Pain Management, Great Ormond Street Hospital for Children, Guildford Street, London, UK.
Wolfson Sensory, Pain and Regeneration Centre, King's College London, Guy's Campus, London, UK.
Eur J Pain. 2025 Mar;29(3):e4775. doi: 10.1002/ejp.4775.
Healthy individuals demonstrate considerable heterogeneity upon dynamic quantitative sensory testing assessment of endogenous pain modulatory mechanisms. For those who stratify into a 'pro-nociceptive profile' cohort, consisting of inefficient conditioned pain modulation (CPM) and elevated temporal summation of pain (TSP), the optimal approach for balancing the net output of pain modulatory processes towards anti-nociception remains unresolved. In this translational healthy human and rat study, we examined whether descending modulation countered spinal amplification during concurrent application of a CPM and TSP paradigm alongside pupillometry since pontine activity was previously linked to functionality of endogenous pain modulatory mechanisms and pupil dilation.
Perceptual (quantitative sensory testing) and spinal neuronal (in vivo electrophysiology) assessment was performed in healthy humans and rats respectively upon application of parallel CPM/diffuse noxious inhibitory controls (cuff algometry) and TSP/wind-up (pinprick) paradigms alongside pupillometry.
In humans, repetitive pinprick stimulation produced TSP while concurrent application of a noxious conditioning stimulus did not affect pain ratings to a single pinprick stimulus, repetitive stimulation or the wind-up ratio. In rats, repetitive pinprick produced neuronal wind-up while concurrent application of a noxious conditioning stimulus inhibited neuronal responses to a single stimulus and repetitive stimulation but not the wind-up ratio. For pupillometry experiments, dilatory responses did not increase during application of a TSP or CPM paradigm in humans, while reliable rat responses were not obtained.
Under the conditions of our study, spinal amplification mechanisms surpassed descending inhibitory controls while pupillometry did not offer a reliable indicator of endogenous pain modulatory mechanism function.
In this translational healthy human and rat study, activity in descending inhibitory controls did not counter spinal amplification processes underpinned by wind up. Despite pupil dilation being previously linked to modulatory mechanisms, dilatory responses did not offer a reliable indicator of functionality. For pro-nociceptive individuals exhibiting inefficient conditioned pain modulation and/or high temporal summation of pain, dampening faciliatory mechanisms rather than augmenting top-down inhibitory processes may be a more effective pain-relief strategy.
在对内源性疼痛调节机制进行动态定量感觉测试评估时，健康个体表现出相当大的异质性。对于那些被归类为“促伤害性感受型”队列的人，即由低效的条件性疼痛调制（CPM）和疼痛时间总和（TSP）升高组成，平衡疼痛调节过程的净输出以实现抗伤害感受的最佳方法仍未解决。在这项转化性健康人类和大鼠研究中，我们研究了在同时应用CPM和TSP范式以及瞳孔测量法时，下行调制是否能对抗脊髓放大，因为脑桥活动先前与内源性疼痛调节机制的功能和瞳孔扩张有关。
在健康人类和大鼠中分别进行了知觉（定量感觉测试）和脊髓神经元（体内电生理学）评估，同时应用平行的CPM/弥漫性有害抑制控制（袖带测痛法）和TSP/风刺激（针刺）范式以及瞳孔测量法。
在人类中，重复性针刺刺激产生了TSP，而同时应用有害条件刺激并未影响对单个针刺刺激、重复性刺激或风刺激比率的疼痛评分。在大鼠中，重复性针刺产生了神经元风刺激，而同时应用有害条件刺激抑制了对单个刺激和重复性刺激的神经元反应，但不影响风刺激比率。对于瞳孔测量实验，在人类应用TSP或CPM范式期间，扩张反应并未增加，而未获得可靠的大鼠反应。
在我们的研究条件下，脊髓放大机制超过了下行抑制控制，而瞳孔测量法并未提供内源性疼痛调节机制功能的可靠指标。
在这项转化性健康人类和大鼠研究中，下行抑制控制的活动并未对抗由风刺激支持的脊髓放大过程。尽管瞳孔扩张先前与调节机制有关，但扩张反应并未提供功能的可靠指标。对于表现出低效条件性疼痛调制和/或高疼痛时间总和的促伤害性感受个体，抑制易化机制而非增强自上而下的抑制过程可能是更有效的疼痛缓解策略。
