Schaefer Charles P, Arkwright Nathan B, Jacobs Leigh M, Jarvis Chelsea K, Hunn Kristen C, Largent-Milnes Tally M, Tome Margaret E, Davis Thomas P
Department of Pharmacology, University of Arizona, Tucson, Arizona, United States of America.
PLoS One. 2018 Feb 7;13(2):e0192340. doi: 10.1371/journal.pone.0192340. eCollection 2018.
The rates of opioid prescription and use have continued to increase over the last few decades resulting in a greater number of opioid tolerant patients. Treatment of acute pain from surgery and injury is a clinical challenge for these patients. Several pain management strategies including prescribing increased opioids are used clinically with limited success; all currently available strategies have significant limitations. Many opioids are a substrate for p-glycoprotein (p-gp), an efflux transporter at the blood-brain barrier (BBB). Increased p-gp is associated with a decreased central nervous system uptake and analgesic efficacy of morphine. Our laboratory previously found that acute peripheral inflammatory pain (PIP) induces p-gp trafficking from the nucleus to the luminal surface of endothelial cells making up the BBB concomitant with increased p-gp activity and decreased morphine analgesic efficacy. In the current study, we tested whether PIP-induced p-gp trafficking could contribute to decreased opioid efficacy in morphine tolerant rats. A 6-day continuous dosing of morphine from osmotic minipumps was used to establish morphine tolerance in female rats. PIP induced p-gp trafficking away from nuclear stores showed a 2-fold increase in morphine tolerant rats. This observation suggests that p-gp trafficking contributes to the decreased morphine analgesic effects in morphine tolerant rats experiencing an acute pain stimulus. Attenuating p-gp trafficking during an acute pain stimulus could improve pain management by increasing the amount of opioid that could reach CNS analgesic targets and decrease the need for the dose escalation that is a serious challenge in pain management.
在过去几十年里，阿片类药物的处方率和使用率持续上升，导致阿片类药物耐受患者数量增多。对这些患者而言，治疗手术和损伤引起的急性疼痛是一项临床挑战。临床上采用了多种疼痛管理策略，包括增加阿片类药物的处方量，但成效有限；目前所有可用策略都有显著局限性。许多阿片类药物是P-糖蛋白（p-gp）的底物，P-糖蛋白是血脑屏障（BBB）处的一种外排转运蛋白。P-糖蛋白增加与吗啡的中枢神经系统摄取减少及镇痛效果降低有关。我们实验室先前发现，急性外周炎性疼痛（PIP）会诱导P-糖蛋白从细胞核转运至构成血脑屏障的内皮细胞腔面，同时P-糖蛋白活性增加，吗啡镇痛效果降低。在本研究中，我们测试了PIP诱导的P-糖蛋白转运是否会导致吗啡耐受大鼠的阿片类药物疗效降低。通过渗透微型泵连续6天给雌性大鼠注射吗啡以建立吗啡耐受性。PIP诱导的P-糖蛋白从核储存处转运，在吗啡耐受大鼠中增加了2倍。这一观察结果表明，P-糖蛋白转运导致了经历急性疼痛刺激的吗啡耐受大鼠的吗啡镇痛效果降低。在急性疼痛刺激期间减弱P-糖蛋白转运，可通过增加能够到达中枢神经系统镇痛靶点的阿片类药物量来改善疼痛管理，并减少剂量递增的需求，而剂量递增是疼痛管理中的一项严峻挑战。
