Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA 94143, USA Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
Pain. 2011 Nov;152(11):2549-2556. doi: 10.1016/j.pain.2011.07.021. Epub 2011 Aug 23.
Chronic pain in adults has been associated with early-life stress. To examine the pronociceptive effect of early-life stress, we evaluated cutaneous and muscle nociception and activity in muscle nociceptors in an animal model of neonatal stress, limited bedding, in the rat. In this neonatal limited bedding (NLB) model, litters are exposed to limited bedding between postnatal days 2 and 9, and controls to standard bedding. In adult NLB-treated rats, mechanical nociceptive threshold in skeletal muscle was significantly lower (22%) than in controls. Furthermore, administration of prostaglandin E(2) in skin as well as muscle produced markedly prolonged hyperalgesia, an effect prevented by spinal intrathecal injection of oligodeoxynucleotide antisense to protein kinase Cε (PKCε), a second messenger in nociceptors that has been implicated in the induction and maintenance of chronic pain. In electrophysiological studies, mechanical threshold of muscle nociceptors was reduced by ~31% and conduction velocity significantly increased (28%). These findings indicate that neonatal stress induces a persistent hyperalgesia and nociceptor sensitization manifest in the adult and that the second messenger PKCε may be a target against which therapies might be directed to treat a chronic pain syndrome that is associated with early-life traumatic stress.
成人慢性疼痛与儿童期应激有关。为了研究儿童期应激的致痛作用，我们在新生限床（NLB）大鼠模型中评估了皮肤和肌肉伤害感受和肌肉伤害感受器的活动。在这种新生限床（NLB）模型中，新生鼠在出生后第 2 至 9 天接受限床暴露，而对照组则接受标准床。在成年 NLB 处理大鼠中，骨骼肌的机械性疼痛阈值显著降低（约 22%）。此外，皮肤和肌肉中前列腺素 E2 的给药导致明显的痛觉过敏延长，这种作用可通过鞘内注射蛋白激酶 Cε（PKCε）反义寡核苷酸来预防，PKCε 是伤害感受器中的第二信使，已被牵连到慢性疼痛的诱导和维持中。在电生理研究中，肌肉伤害感受器的机械阈值降低约 31%，传导速度显著增加（约 28%）。这些发现表明，新生期应激会导致成年后持续的痛觉过敏和伤害感受器敏化，而第二信使 PKCε 可能是治疗与儿童期创伤性应激相关的慢性疼痛综合征的靶点。
