Heterogeneity in patterns of pain development after nerve injury in rats and the influence of sex.
Heterogeneity in patterns of pain development after nerve injury in rats and the influence of sex.
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DOI：
10.1016/j.ynpai.2021.100069
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Dean C
中科院分区：
文献类型：
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作者：
Sherman K;Woyach V;Eisenach JC;Hopp FA;Cao F;Hogan QH;Dean C
建模强调了均匀神经损伤后痛觉过敏的异质性。时间表型中的性别差异很明显。自主功能的变化可能与感觉轨迹相关。感觉个性可能会影响疼痛管理策略。神经性疼痛的起源很复杂，因为不同或相似病因的患者之间的感觉异常可能有所不同，这表明机械异质性，这是一个很大程度上尚未探索的概念。然而，数据通常基于它们具有相同的潜在发病机制的假设进行分组进行分析。性别是可能导致疼痛反应差异的一个因素。神经性疼痛在女性患者中更为普遍，但可以在受控环境中检查疼痛发展的临床前研究通常未能包括女性受试者。本研究探讨了雄性和雌性大鼠神经病理性疼痛模型（幸免神经损伤，SNI）中由有害机械刺激引起的痛觉过敏样行为（HLB）的发展模式，以及与慢性疼痛相关的自主神经功能障碍。使用离散混合模型和基于规则的纵向聚类对 HLB 进行跨时间分析。两种方法都确定了 SNI 后痛觉过敏轨迹的相似分组，当数据仅按性别分组时，这些分组并不明显。在同一痛觉过敏发生组中，混合模型显示，女性 HLB 的发生相对于男性延迟，并达到与男性相似或更高的程度。数据还表明，在 HLB 发生之前或开始时，交感神经张力（如心率变异性所示）降至 SNI 前水平以下。本研究对 HLB 个体发展的异质性进行了分类，并确定了神经损伤后神经病理性疼痛发展时间过程中的性别二态性。未来研究解决这些差异背后的机制可能有助于适当的疼痛治疗。
Modeling highlights heterogeneity in hyperalgesia after uniform nerve injury. Sex differences are apparent in the temporal phenotypes. Changes in autonomic function may correlate to sensory trajectories. Sensory individuality could impact strategies for pain management. The genesis of neuropathic pain is complex, as sensory abnormalities may differ between patients with different or similar etiologies, suggesting mechanistic heterogeneity, a concept that is largely unexplored. Yet, data are usually grouped for analysis based on the assumption that they share the same underlying pathogenesis. Sex is a factor that may contribute to differences in pain responses. Neuropathic pain is more prevalent in female patients, but pre-clinical studies that can examine pain development in a controlled environment have typically failed to include female subjects. This study explored patterns of development of hyperalgesia-like behavior (HLB) induced by noxious mechanical stimulation in a neuropathic pain model (spared nerve injury, SNI) in both male and female rats, and autonomic dysfunction that is associated with chronic pain. HLB was analyzed across time, using both discrete mixture modeling and rules-based longitudinal clustering. Both methods identified similar groupings of hyperalgesia trajectories after SNI that were not evident when data were combined into groups by sex only. Within the same hyperalgesia development group, mixed models showed that development of HLB in females was delayed relative to males and reached a magnitude similar to or higher than males. The data also indicate that sympathetic tone (as indicated by heart rate variability) drops below pre-SNI level before or at the onset of development of HLB. This study classifies heterogeneity in individual development of HLB and identifies sexual dimorphism in the time course of development of neuropathic pain after nerve injury. Future studies addressing mechanisms underlying these differences could facilitate appropriate pain treatments.