Department of Anesthesiology, Peking Union Medical College Hospital, Beijing, 100730, China.
Department of Anesthesiology, The first hospital of Jilin University, Changchun, Jilin, 130021, China.
Mol Brain. 2018 Jun 28;11(1):35. doi: 10.1186/s13041-018-0379-2.
Pruritus is the most common complication of intrathecal morphine; however, its exact molecular mechanism is unclear, and treatment is challenging. The analgesic effect of N-methyl-D-aspartate (NMDA) receptor antagonists and the morphine-associated increase in NMDA receptor activation suggest potential role of NMDA receptor in the spinal itch sensation. Male C57BL/6 mice were given intrathecal morphine to induce scratching behavior. The effects of NMDA, ketamine, ifenprodil and U0126 on morphine-induced pruritus and analgesia were evaluated also. The number of scratching responses was counted for 30 min post-injection to evaluate pruritus. A warm-water tail immersion assay was conducted before and until 120 min post-injection at 30-min intervals. Percent of maximal possible effect (%MPE) and area under curve (AUC) were calculated based on tail-flick latency to evaluate analgesic efficacy. Compared with control treatment, intrathecal morphine elicited an obvious scratching response and analgesic effect in a dose dependent manner. Ketamine (1 μg), ifenprodil (0.1 μg) and U0126 (0.1 μg and 1.0 μg) all significantly attenuated morphine induced scratches. Ifenprodil (0.1 μg) injection significantly prolonged the analgesic effect of intrathecal morphine. The ERK1/2 phosphorylation induced by intrathecal morphine was inhibited by ketamine, ifenprodil and U0126 as well. U0126 inhibited morphine-induced pruritus with no effect on its analgesia. Therefore, intrathecal coadministration of morphine with NMDA receptor antagonists ketamine and ifenprodil alleviated morphine-induced scratching. Intrathecal morphine increased ERK phosphorylation in the lumbar spinal dorsal horn, which may be related with morphine-induced pruritus, and was counteracted by NMDA receptor antagonists.
瘙痒是鞘内吗啡最常见的并发症；然而，其确切的分子机制尚不清楚，治疗也具有挑战性。N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的镇痛作用以及吗啡引起的 NMDA 受体激活增加表明 NMDA 受体在脊髓瘙痒感觉中可能起作用。雄性 C57BL/6 小鼠鞘内给予吗啡诱导搔抓行为。还评估了 NMDA、氯胺酮、ifenprodil 和 U0126 对吗啡诱导的瘙痒和镇痛的影响。注射后 30 分钟内计数搔抓反应次数以评估瘙痒。在注射前和 120 分钟内每隔 30 分钟进行一次温水尾巴浸泡试验。根据尾巴摆动潜伏期计算最大可能效应百分比（%MPE）和曲线下面积（AUC），以评估镇痛效果。与对照治疗相比，鞘内吗啡呈剂量依赖性地引起明显的搔抓反应和镇痛作用。氯胺酮（1μg）、ifenprodil（0.1μg）和 U0126（0.1μg 和 1.0μg）均显著减轻吗啡引起的搔抓。ifenprodil（0.1μg）注射显著延长鞘内吗啡的镇痛作用。鞘内吗啡诱导的 ERK1/2 磷酸化也被氯胺酮、ifenprodil 和 U0126 抑制。U0126 抑制吗啡诱导的瘙痒而不影响其镇痛作用。因此，鞘内给予吗啡与 NMDA 受体拮抗剂氯胺酮和 ifenprodil 共同给药可减轻吗啡引起的搔抓。鞘内吗啡增加了腰脊髓背角的 ERK 磷酸化，这可能与吗啡引起的瘙痒有关，并被 NMDA 受体拮抗剂拮抗。
