Macey Tara A, Bobeck Erin N, Hegarty Deborah M, Aicher Sue A, Ingram Susan L, Morgan Michael M
Department of Psychology, Washington State University Vancouver, Vancouver, Washington 98686, USA.
J Pharmacol Exp Ther. 2009 Nov;331(2):412-8. doi: 10.1124/jpet.109.152157. Epub 2009 Aug 14.
Repeated administration of opioids produces long-lasting changes in micro-opioid receptor (MOR) signaling that underlie behavioral changes such as tolerance. Mitogen-activated protein kinase (MAPK) pathways, including MAPK extracellular signal-regulated kinases (ERK1/2), are modulated by opioids and are known to produce long-lasting changes in cell signaling. Thus, we tested the hypothesis that ERK1/2 activation contributes to the development and/or expression of morphine tolerance mediated by the periaqueductal gray (PAG). Changes in phosphorylated ERK1/2 expression were assessed with confocal microscopy and compared to behavioral measures of tolerance to the antinociceptive effects of chronic morphine administration. Repeated microinjection of morphine into the PAG produced tolerance and caused a significant increase in ERK1/2 phosphorylation, an effect not evident with acute morphine microinjection. Microinjection of the MAPK/ERK kinase inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene ethanolate (U0126), into the PAG had no effect on antinociception produced by acute morphine administration. However, repeated coadministration of U0126 and morphine into the PAG blocked ERK1/2 phosphorylation and enhanced the development of morphine tolerance. Coadministration of U0126 with morphine only on the test day also enhanced the expression of morphine tolerance. Administration of the irreversible opioid receptor antagonist beta-chlornaltrexamine blocked the activation of ERK1/2 caused by repeated morphine microinjections, demonstrating that ERK1/2 activation was a MOR-mediated event. In summary, these studies show that chronic morphine administration alters ERK1/2 signaling and that disruption of ERK1/2 signaling enhances both the development and expression of morphine tolerance. Contrary to expectations, these data indicate that ERK1/2 activation opposes the development of morphine tolerance.
反复给予阿片类药物会在微阿片受体（MOR）信号传导中产生持久变化，这些变化是诸如耐受性等行为改变的基础。丝裂原活化蛋白激酶（MAPK）途径，包括MAPK细胞外信号调节激酶（ERK1/2），受阿片类药物调节，并且已知会在细胞信号传导中产生持久变化。因此，我们测试了以下假设：ERK1/2激活有助于导水管周围灰质（PAG）介导的吗啡耐受性的发展和/或表达。用共聚焦显微镜评估磷酸化ERK1/2表达的变化，并与慢性吗啡给药的抗伤害感受作用的耐受性行为测量结果进行比较。向PAG反复微量注射吗啡会产生耐受性，并导致ERK1/2磷酸化显著增加，急性吗啡微量注射则无此明显效果。向PAG微量注射MAPK/ERK激酶抑制剂1,4 - 二氨基 - 2,3 - 二氰基 - 1,4 - 双（邻氨基苯基巯基）丁二烯乙醇酸盐（U0126）对急性吗啡给药产生的抗伤害感受没有影响。然而，将U0126与吗啡反复共同给药至PAG可阻断ERK1/2磷酸化，并增强吗啡耐受性的发展。仅在测试日将U0126与吗啡共同给药也增强了吗啡耐受性的表达。给予不可逆的阿片受体拮抗剂β - 氯诺昔明可阻断反复吗啡微量注射引起的ERK1/2激活，表明ERK1/2激活是MOR介导的事件。总之，这些研究表明慢性吗啡给药会改变ERK1/2信号传导，而ERK1/2信号传导的破坏会增强吗啡耐受性的发展和表达。与预期相反，这些数据表明ERK1/2激活会对抗吗啡耐受性的发展。
