Davis Seth M, Zuke Jared T, Berchulski Mariah R, Burman Michael A
Department of Psychology, University of New England, Biddeford, ME, United States.
Center for Excellence in the Neurosciences, University of New England, Biddeford, ME, United States.
Front Physiol. 2021 May 11;12:660792. doi: 10.3389/fphys.2021.660792. eCollection 2021.
Neonatal pain such as that experienced by infants in the neonatal intensive care unit is known to produce later-life dysfunction including heightened pain sensitivity and anxiety, although the mechanisms remain unclear. Both chronic pain and stress in adult organisms are known to influence the corticotropin-releasing factor (CRF) system in the Central Nucleus of the Amygdala, making this system a likely candidate for changes following neonatal trauma. To examine this, neonatal rats were subjected to daily pain, non-painful handling or left undisturbed for the first week of life. Beginning on postnatal day, 24 male and female rats were subjected to a 4-day fear conditioning and sensory testing protocol. Some subjects received intra-amygdalar administration of either Vehicle, the CRF receptor 1 (CRF) receptor antagonist Antalarmin, or the CRF receptor 2 (CRF) receptor antagonist Astressin 2B prior to fear conditioning and somatosensory testing, while others had tissue collected following fear conditioning and CRF expression in the CeA and BLA was assessed using fluorescent hybridization. CRF antagonism attenuated fear-induced hypersensitivity in neonatal pain and handled rats, while CRF antagonism produced a general antinociception. In addition, neonatal pain and handling produced a lateralized sex-dependent decrease in CRF expression, with males showing a diminished number of CRF-expressing cells in the right CeA and females showing a similar reduction in the number of CRF-expressing cells in the left BLA compared to undisturbed controls. These data show that the amygdalar CRF system is a likely target for alleviating dysfunction produced by early life trauma and that this system continues to play a major role in the lasting effects of such trauma into the juvenile stage of development.
新生儿重症监护病房中的婴儿所经历的新生儿疼痛，已知会导致日后生活出现功能障碍，包括疼痛敏感性增强和焦虑，尽管其机制尚不清楚。已知成年生物体中的慢性疼痛和应激都会影响杏仁核中央核中的促肾上腺皮质激素释放因子（CRF）系统，这使得该系统可能是新生儿创伤后发生变化的一个候选因素。为了对此进行研究，新生大鼠在出生后的第一周每天接受疼痛刺激、非疼痛性处理或不做处理。从出生后第24天开始，对雄性和雌性大鼠进行为期4天的恐惧条件反射和感觉测试方案。在恐惧条件反射和体感测试之前，一些实验对象接受杏仁核内注射溶媒、CRF受体1（CRF1）受体拮抗剂安他敏或CRF受体2（CRF2）受体拮抗剂阿斯特辛2B，而其他实验对象在恐惧条件反射后收集组织，并使用荧光杂交评估中央杏仁核（CeA）和基底外侧杏仁核（BLA）中的CRF表达。CRF拮抗作用减弱了新生期疼痛和接受处理的大鼠中恐惧诱导的超敏反应，而CRF拮抗作用产生了一般的抗伤害感受作用。此外，新生期疼痛和处理导致CRF表达出现性别依赖性的侧化减少，与未受干扰的对照组相比，雄性大鼠右侧CeA中表达CRF的细胞数量减少，雌性大鼠左侧BLA中表达CRF的细胞数量出现类似减少。这些数据表明，杏仁核CRF系统可能是减轻早期生活创伤所产生功能障碍的一个靶点，并且该系统在这种创伤对发育至幼年期的持久影响中继续发挥主要作用。
