Matsuda Keiichiro, Sasaki Mika, Baba Hiroshi, Kamiya Yoshinori
Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
J Pain. 2022 Oct;23(10):1765-1778. doi: 10.1016/j.jpain.2022.06.001. Epub 2022 Jun 12.
Dexamethasone supplementation to local anesthetics prolongs its action, yet the underlying mechanism is unclear. Previous studies have reported that increased p-p38 mitogen-activated protein kinase (MAPK) in the dorsal root ganglia (DRG) is associated with pain-associated behavior and that nitric oxide (NO), which is known to be a pronociceptive substance, directly inhibits sciatic nerve conduction. Here, we investigated the temporal changes in the hyperalgesic effect and p-p38 MAPK and NO synthase (NOS) expression levels in the DRG when dexamethasone was added to ropivacaine used for a sciatic nerve block (SNB) in postoperative pain model mice. Dexamethasone supplementation to ropivacaine significantly prolonged the analgesic effect of SNB via glucocorticoid receptor activation. Histological examination revealed that ropivacaine suppressed p-p38 MAPK expression in the DRG regardless of dexamethasone supplementation, suggesting that p-p38 MAPK was not involved in the prolonging effect of dexamethasone on nerve block. Contrastingly, plantar incision markedly increased the expression of neuronal NOS (nNOS) in DRG, and dexamethasone supplementation to ropivacaine significantly suppressed nNOS expression. Supplementation of L-NAME, an inhibitor of NOS, to ropivacaine markedly prolonged the effect of SNB, similar to dexamethasone. These results suggest that dexamethasone supplementation to local anesthetics prolongs the analgesic effect by inhibiting nNOS activity. PERSPECTIVE: The current study revealed that dexamethasone supplementation to local anesthetics prolongs the analgesic effect by inhibiting the activity of neuronal NOS and that p-p38 MAPK may not be involved in this phenomenon. Our findings offer a new target for the discovery of long-acting local anesthetics.
在局部麻醉药中添加地塞米松可延长其作用时间，但其潜在机制尚不清楚。先前的研究报道，背根神经节（DRG）中磷酸化p38丝裂原活化蛋白激酶（MAPK）增加与疼痛相关行为有关，并且已知作为伤害感受性物质的一氧化氮（NO）直接抑制坐骨神经传导。在此，我们研究了在术后疼痛模型小鼠中，将地塞米松添加到用于坐骨神经阻滞（SNB）的罗哌卡因中时，DRG中痛觉过敏效应以及p-p38 MAPK和一氧化氮合酶（NOS）表达水平的时间变化。在罗哌卡因中添加地塞米松可通过糖皮质激素受体激活显著延长SNB的镇痛作用。组织学检查显示，无论是否添加地塞米松，罗哌卡因均可抑制DRG中p-p38 MAPK的表达，这表明p-p38 MAPK不参与地塞米松对神经阻滞的延长作用。相反，足底切口显著增加了DRG中神经元型NOS（nNOS）的表达，而在罗哌卡因中添加地塞米松可显著抑制nNOS的表达。向罗哌卡因中添加NOS抑制剂L-NAME可显著延长SNB的作用，类似于地塞米松。这些结果表明，在局部麻醉药中添加地塞米松可通过抑制nNOS活性来延长镇痛作用。观点：当前研究表明，在局部麻醉药中添加地塞米松可通过抑制神经元型NOS的活性来延长镇痛作用，并且p-p38 MAPK可能不参与此现象。我们的发现为长效局部麻醉药的研发提供了新的靶点。
