The aged population has a higher probability of developing chronic pain from acute insults because of age-associated low-grade inflammation. Several emerging studies have shown a crucial role of cap-dependent translation in the development of chronic pain in young adult animals; however, its role in the aged has never been reported. Acute and chronic inflammatory responses, including pain, are altered over age, and understanding how cap-dependent translation can represent an important and druggable pathway is imperative for understanding its therapeutic potential. Here we have tested how an inflammatory stimulus, complete Freund’s adjuvant (CFA), affects spontaneous and evoked pain, as well as inflammation in young versus aged mice that lack functional cap-dependent translation machinery (eukaryotic translation initiation factor 4E (eIF4E)) compared with age-matched wild-type (WT) mice. Interestingly, we found that CFA-induced acute pain and inflammation are modulated by eIF4E phosphorylation in aged but not young animals. Aged transgenic animals showed attenuated paw temperature and inflammation, as well as a mitigation in the onset and quicker resolution in mechanical and thermal hypersensitivity. We found that levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α are elevated in dorsal root ganglia in aged WT and eIF4E transgenic groups, despite faster resolution of acute inflammation and pain in the aged eIF4E transgenic animals. We propose that these cytokines are important in mediating the observed behavioral responses in the young and represent an alternate pathway in the development of age-associated inflammation and behavioral consequences. These findings demonstrate that eIF4E phosphorylation can be a key target for treating inflammatory pain in the aged.

由于与年龄相关的低度炎症，老年人群因急性损伤而发展为慢性疼痛的可能性更高。几项新兴研究表明，帽依赖性翻译在年轻成年动物慢性疼痛的发展中起着至关重要的作用。然而，它在老年人中的作用从未被报道过。包括疼痛在内的急性和慢性炎症反应会随着年龄的增长而改变，了解帽依赖性翻译如何代表一个重要且可药物化的途径对于了解其治疗潜力至关重要。在这里，我们测试了炎症刺激，完全弗氏佐剂 (CFA)，如何影响自发性和诱发性疼痛，以及与年龄匹配的野生型 (WT) 小鼠相比，缺乏功能性帽依赖性翻译机制（真核翻译起始因子 4E (eIF4E)）的年轻与老年小鼠的炎症。有趣的是，我们发现 CFA 诱导的急性疼痛和炎症受 eIF4E 磷酸化的调节，在老年但不是年轻动物。老年转基因动物表现出减轻的爪子温度和炎症，以及机械和热超敏反应的发病缓解和更快的解决。我们发现，尽管老年 eIF4E 转基因动物的急性炎症和疼痛消退更快，但老年 WT 和 eIF4E 转基因组的背根神经节中的白细胞介素 (IL)-1β 和肿瘤坏死因子 (TNF)-α 水平升高。我们提出这些细胞因子在介导观察到的年轻人行为反应中很重要，并且代表了与年龄相关的炎症和行为后果发展的替代途径。这些发现表明，eIF4E 磷酸化可以成为治疗老年人炎症性疼痛的关键靶点。