Université de Caen, Laboratoire de signalisation, Électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, UPRES EA 4650, IFR 146 ICORE, Avenue côte de Nacre, 14032 Caen, France.
Neuropharmacology. 2013 Oct;73:368-79. doi: 10.1016/j.neuropharm.2013.06.010. Epub 2013 Jun 21.
Remifentanil is a powerful mu-opioid (MOP) receptor agonist used in anaesthesia with a very short half-life. However, per-operative perfusion of remifentanil was shown to increase morphine consumption during post-operative period to relieve pain. In the present study, we aimed to describe the cellular mechanisms responsible for this apparent reduction of morphine efficacy. For this purpose, we first examined the pharmacological properties of both remifentanil and morphine at the MOP receptor, endogenously expressed in the human neuroblastoma SH-SY5Y cell line, to regulate adenylyl cyclase and the MAP kinase ERK1/2 pathway, their potency to promote MOP receptor phosphorylation, arrestin 3-CFP (cyan fluorescent protein) recruitment and receptor trafficking during acute and sustained exposure. In the second part of this work, we studied the effects of a prior exposure of remifentanil on morphine-induced inhibition of cAMP accumulation, activation of ERK1/2 and analgesia. We showed that sustained exposure to remifentanil promoted a rapid desensitization of opioid receptors on both signalling pathways and a pretreatment with this agonist reduced signal transduction produced by a second challenge with morphine. While both opioid agonists promoted Ser(375) phosphorylation on MOP receptor, remifentanil induced a rapid internalization of opioid receptors compared to morphine but without detectable arrestin 3-CFP translocation to the plasma membrane in our experimental conditions. Lastly, a cross-tolerance between remifentanil and morphine was observed in mice using the hot plate test. Our in vitro and in vivo data thus demonstrated that remifentanil produced a rapid desensitization and internalization of the MOP receptor that would reduce the anti-nociceptive effects of morphine.
瑞芬太尼是一种作用于μ-阿片受体（MOP）的强效激动剂，在麻醉中具有非常短的半衰期。然而，术中瑞芬太尼灌注被证明会增加术后吗啡的消耗，以缓解疼痛。在本研究中，我们旨在描述负责这种明显降低吗啡疗效的细胞机制。为此，我们首先检查了瑞芬太尼和吗啡在人神经母细胞瘤 SH-SY5Y 细胞系中内源性表达的 MOP 受体上的药理学特性，以调节腺苷酸环化酶和 MAP 激酶 ERK1/2 途径，它们促进 MOP 受体磷酸化、招募 arrestin 3-CFP（青色荧光蛋白）和受体在急性和持续暴露期间的转运的效力。在这项工作的第二部分中，我们研究了瑞芬太尼预先暴露对吗啡诱导的 cAMP 积累抑制、ERK1/2 激活和镇痛的影响。我们表明，持续暴露于瑞芬太尼促进了两种信号通路中阿片受体的快速脱敏，并且用这种激动剂预处理会降低第二次用吗啡挑战时产生的信号转导。虽然两种阿片类激动剂都促进 MOP 受体上 Ser(375)的磷酸化，但与吗啡相比，瑞芬太尼诱导阿片受体的快速内化，但在我们的实验条件下没有检测到 arrestin 3-CFP 向质膜易位。最后，在使用热板试验的小鼠中观察到瑞芬太尼和吗啡之间的交叉耐受。我们的体外和体内数据表明，瑞芬太尼会导致 MOP 受体的快速脱敏和内化，从而降低吗啡的抗伤害感受作用。
