Department of Anaesthesiology, Institut Municipal d'Investigació Mèdica-Hospital del Mar, Universitat Autònoma de Barcelona, Paseo Marítimo 25, 08003, Barcelona, Spain.
Naunyn Schmiedebergs Arch Pharmacol. 2012 Apr;385(4):397-409. doi: 10.1007/s00210-011-0721-z. Epub 2011 Dec 30.
Tissue injury and/or opioids induce plastic changes in the spinal cord resulting in pain hypersensitivity; the contribution of the dorsal root ganglia (DRG) is poorly understood. We evaluated DRG phenotypic changes induced by surgery and/or remifentanil in a mice model of postoperative pain using as neuronal markers ERK1/2 and c-Fos; prodynorphin mRNA and dynorphin levels were also determined. We hypothesized that a correlation between nociception and DRG reactivity would occur. Surgery and/or remifentanil induced mechanical hypersensitivity, correlated with ERK1/2 phosphorylation and c-Fos expression in the DRG; changes were greater in the remifentanil + incision group and still present on day 14 (p < 0.01 vs. control). Intrathecal PD98059 (ERK1/2 inhibitor) partially reversed the mechanical hypersensitivity (44%, p < 0.05) observed in the remifentanil + incision group. In this group, significant increases in prodynorphin mRNA (at 2, 7, and 14 days, p < 0.01) roughly coincided with increases in dynorphin (days 2 and 14, p < 0.001) in the DRG. Remifentanil or incision (alone) also induced an up-regulation in prodynorphin mRNA expression on days 7 and 14 (p < 0.01, p < 0.05, respectively), partially correlating with dynorphin levels. On day 21, all molecular changes returned to control levels in all experimental conditions, concurring with the complete recovery of nociceptive thresholds. Surgery and/or remifentanil induce up-regulation of c-Fos and pERK in the DRG, approximately correlating with nociceptive behavior, also associated with an increased expression of prodynorphin/dynorphin. These changes support the role of the DRG in the development and maintenance of pain hypersensitivity after surgery. The findings could contribute to the development of new therapeutic agents focused on peripheral targets.
组织损伤和/或阿片类药物会导致脊髓产生可塑性变化，从而导致痛觉过敏；而背根神经节（DRG）的作用则知之甚少。我们使用 ERK1/2 和 c-Fos 作为神经元标志物，评估了手术后疼痛小鼠模型中手术和/或瑞芬太尼引起的 DRG 表型变化；还测定了前原啡肽 mRNA 和强啡肽水平。我们假设疼痛和 DRG 反应之间存在相关性。手术和/或瑞芬太尼引起机械性痛觉过敏，与 DRG 中的 ERK1/2 磷酸化和 c-Fos 表达相关；在瑞芬太尼+切口组中变化更大，在第 14 天仍存在（与对照组相比，p<0.01）。鞘内给予 PD98059（ERK1/2 抑制剂）部分逆转了瑞芬太尼+切口组观察到的机械性痛觉过敏（44%，p<0.05）。在该组中，DRG 中前原啡肽 mRNA 显著增加（在第 2、7 和 14 天，p<0.01），大致与强啡肽的增加相吻合（在第 2 和 14 天，p<0.001）。瑞芬太尼或切口（单独）也在第 7 和 14 天诱导前原啡肽 mRNA 表达上调（p<0.01，p<0.05），与强啡肽水平部分相关。在第 21 天，在所有实验条件下，所有分子变化均恢复至对照水平，与疼痛阈值完全恢复一致。手术和/或瑞芬太尼诱导 DRG 中 c-Fos 和 pERK 的上调，与痛觉行为大致相关，也与前原啡肽/强啡肽表达增加相关。这些变化支持 DRG 在手术后痛觉过敏的发展和维持中的作用。这些发现可能有助于开发针对外周靶点的新型治疗药物。
