Boullon Laura, Finn David P, Llorente-Berzal Álvaro
Department of Pharmacology and Therapeutics, School of Medicine, Centre for Pain Research and Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.
Front Pain Res (Lausanne). 2021 Jun 4;2:673638. doi: 10.3389/fpain.2021.673638. eCollection 2021.
Chronic neuropathic pain is a major unmet clinical need affecting 10% of the world population, the majority of whom suffer from co-morbid mood disorders. Sex differences have been reported in pain prevalence, perception and response to analgesics. However, sexual dimorphism in chronic neuropathic pain and the associated neurobiology, are still poorly understood. The lack of efficacy and the adverse effects associated with current pharmacological treatments, further underline the need for new therapeutic targets. The endocannabinoid system (ECS) is a lipid signalling system which regulates a large number of physiological processes, including pain. The aim of this study was to investigate sexual dimorphism in pain-, anxiety- and depression-related behaviours, and concomitant alterations in supraspinal and spinal endocannabinoid levels in the spared nerve injury (SNI) animal model of peripheral neuropathic pain. Sham or SNI surgery was performed in adult male and female Sprague-Dawley rats. Mechanical and cold allodynia was tested weekly using von Frey and acetone drop tests, respectively. Development of depression-related behaviours was analysed using sucrose splash and sucrose preference tests. Locomotor activity and anxiety-related behaviours were assessed with open field and elevated plus maze tests. Levels of endocannabinoid ligands and related -acylethanolamines in supraspinal regions of the descending inhibitory pain pathway, and spinal cord, were analysed 42 days post-surgery. SNI surgery induced allodynia in rats of both sexes. Female-SNI rats exhibited earlier onset and greater sensitivity to cold and mechanical allodynia than their male counterparts. In male rats, SNI induced a significant reduction of rearing, compared to sham controls. Trends for depressive-like behaviours in females and for anxiety-like behaviours in males were observed after SNI surgery but did not reach statistical significance. No concomitant alterations in levels of endogenous cannabinoid ligands and related -acylethanolamines were observed in the regions analysed. Our results demonstrate differential development of SNI-induced nociceptive behaviour between male and female rats suggesting important sexually dimorphic modifications in pain pathways. SNI had no effect on depression- or anxiety-related behaviours in animals of either sex, or on levels of endocannabinoid ligands and related -acylethanolamines across the regions involved in the descending modulation of nociception at the time points investigated.
慢性神经性疼痛是一项尚未满足的重大临床需求，影响着全球10%的人口，其中大多数人同时患有情绪障碍。在疼痛患病率、疼痛感知以及对镇痛药的反应方面，已有性别差异的报道。然而，慢性神经性疼痛中的性别二态性及其相关神经生物学仍未得到充分了解。当前药物治疗缺乏疗效且存在不良反应，这进一步凸显了寻找新治疗靶点的必要性。内源性大麻素系统（ECS）是一种脂质信号系统，可调节包括疼痛在内的大量生理过程。本研究的目的是在周围神经性疼痛的 spared nerve injury（SNI）动物模型中，研究疼痛、焦虑和抑郁相关行为的性别二态性，以及脊髓上和脊髓内源性大麻素水平的伴随变化。对成年雄性和雌性Sprague-Dawley大鼠进行假手术或SNI手术。每周分别使用von Frey和丙酮滴注试验测试机械性和冷痛觉过敏。使用蔗糖飞溅和蔗糖偏好试验分析抑郁相关行为的发展。通过旷场试验和高架十字迷宫试验评估运动活动和焦虑相关行为。在手术后42天分析下行抑制性疼痛通路的脊髓上区域和脊髓内源性大麻素配体及相关酰基乙醇胺的水平。SNI手术在两性大鼠中均诱发了痛觉过敏。雌性SNI大鼠比雄性SNI大鼠表现出更早的发作和对冷和机械性痛觉过敏更高的敏感性。与假手术对照组相比，SNI使雄性大鼠的竖毛显著减少。SNI手术后观察到雌性大鼠有类似抑郁行为的趋势，雄性大鼠有类似焦虑行为的趋势，但未达到统计学显著性。在所分析的区域中，未观察到内源性大麻素配体和相关酰基乙醇胺水平的伴随变化。我们的结果表明，雄性和雌性大鼠之间SNI诱发的伤害性感受行为存在差异发展，提示疼痛通路中存在重要的性别二态性改变。在所研究的时间点，SNI对两性动物的抑郁或焦虑相关行为，以及对参与伤害性感受下行调制的各区域内源性大麻素配体和相关酰基乙醇胺水平均无影响。
