Garcia M M, Anderson A T, Edwards R, Harlan R E
Department of Otolaryngology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, USA.
Neuroscience. 2003;119(3):787-94. doi: 10.1016/s0306-4522(02)00975-2.
Acute injection of morphine induces expression of the immediate-early genes c-Fos and JunB in several forebrain regions of the rat, in part through an N-methyl-D-aspartate (NMDA) receptor-dependent mechanism. Because membrane depolarization through (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors is believed to be necessary for full activation of NMDA receptors, we determined the role of AMPA receptors in morphine-induced c-Fos expression. Rats were given the AMPA receptor antagonist GYKI-52466 (12.9 mg/kg, i.p.) 15 min before morphine (10 mg/kg, s.c.), or the AMPA receptor enhancer CX516 (30 mg/kg, i.p.) 5 min after morphine. The c-Fos response was attenuated by the antagonist and augmented by the enhancer. Using double immunocytochemistry, we found that morphine induced c-Fos in neurons containing the GluR2/3, but not the GluR1 and rarely the GluR4, subunits of the AMPA receptor. Double immunocytochemistry for mu opioid receptor and c-Fos showed that c-Fos expression was mainly absent in the patch compartment of the striatum, which is enriched in mu opioid receptors. The glutamatergic synapse often contains metabotropic receptors as well as ionotropic receptors. Type I metabotropic glutamate receptors are coupled to activation of protein kinase C, which has also been shown to mediate the immediate-early gene response to morphine. To determine if activation of metabotropic glutamate receptors is involved in rapid effects of morphine on the brain, rats were given the type I metabotropic glutamate receptor antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 0.2 mg/kg, i.p.) or vehicle 30 min before morphine treatment. Pretreatment with AIDA completely blocked morphine-induced c-Fos expression in the caudate-putamen.Taken together, these results demonstrate involvement of both AMPA and type I metabotropic glutamate receptors in the acute effects of morphine on the forebrain, supporting an important role for glutamatergic neurotransmission mediated by non-NMDA glutamate receptors in morphine's actions.
急性注射吗啡可诱导大鼠前脑多个区域即刻早期基因c-Fos和JunB的表达，部分是通过N-甲基-D-天冬氨酸（NMDA）受体依赖性机制实现的。由于据信通过（RS）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）谷氨酸受体的膜去极化对于NMDA受体的完全激活是必需的，我们确定了AMPA受体在吗啡诱导的c-Fos表达中的作用。在注射吗啡（10 mg/kg，皮下注射）前15分钟给大鼠腹腔注射AMPA受体拮抗剂GYKI-52466（12.9 mg/kg），或在注射吗啡后5分钟腹腔注射AMPA受体增强剂CX516（30 mg/kg）。拮抗剂减弱了c-Fos反应，而增强剂增强了该反应。通过双重免疫细胞化学，我们发现吗啡在含有AMPA受体GluR2/3亚基的神经元中诱导c-Fos表达，但在含有GluR1亚基的神经元中未诱导，且很少在含有GluR4亚基的神经元中诱导。μ阿片受体和c-Fos的双重免疫细胞化学显示，c-Fos表达在富含μ阿片受体的纹状体斑块区基本不存在。谷氨酸能突触通常同时含有代谢型受体和离子型受体。I型代谢型谷氨酸受体与蛋白激酶C的激活偶联，蛋白激酶C也已被证明介导对吗啡的即刻早期基因反应。为了确定代谢型谷氨酸受体的激活是否参与吗啡对大脑的快速作用，在吗啡处理前30分钟给大鼠腹腔注射I型代谢型谷氨酸受体拮抗剂（RS）-1-氨基茚满-1,5-二羧酸（AIDA；0.2 mg/kg）或赋形剂。用AIDA预处理完全阻断了吗啡诱导的尾状核-壳核中c-Fos的表达。综上所述，这些结果表明AMPA和I型代谢型谷氨酸受体均参与了吗啡对前脑的急性作用，支持非NMDA谷氨酸受体介导的谷氨酸能神经传递在吗啡作用中起重要作用。
