Martin G, Nie Z, Siggins G R
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
J Neurosci. 1997 Jan 1;17(1):11-22. doi: 10.1523/JNEUROSCI.17-01-00011.1997.
The nucleus accumbens (NAcc) may play a major role in opiate dependence, and central NMDA receptors are reported to influence opiate tolerance and dependence. Therefore, we investigated the effects of the selective mu-opioid receptor agonist [D-Ala2-N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO) on membrane properties of rat NAcc neurons and on events mediated by NMDA and non-NMDA glutamate receptors, using intracellular recording in a brain slice preparation. Most NAcc neurons showed a marked inward rectification (correlated with Cs+- and Ba2+-sensitive inward relaxations) when hyperpolarized, as well as a slowly depolarizing ramp with positive current pulses. Superfusion of DAMGO did not alter membrane potential, input resistance, or the inward relaxations. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) used to block non-NMDA glutamate receptors and bicuculline to block GABAA receptors, EPSPs evoked by local stimulation displayed characteristics of an NMDA component: (1) long duration, (2) voltage sensitivity, and (3) blockade by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (D-APV). DAMGO (0.1-1 muM) significantly decreased both NMDA- and non-NMDA-EPSP amplitudes with reversal of this effect by naloxone and the mu-selective antagonist [Cys2-Tyr3-Orn5-Pen7]-somatostatinamide (CTOP). To assess a postsynaptic action of DAMGO, we superfused slices with tetrodotoxin and evoked inward currents by local application of glutamate agonists. Surprisingly, 0.1-1 microM DAMGO markedly enhanced the NMDA currents (with reversal by CTOP) but reduced the non-NMDA currents. At higher concentrations (5 microM), DAMGO reduced NMDA currents, but this effect was enhanced, not blocked, by CTOP. These results indicate a complex DAMGO modulation of the NMDA component of glutamatergic synaptic transmission in NAcc: mu receptor activation decreases NMDA-EPSP amplitudes presynaptically yet increases NMDA currents postsynaptically. These new data may provide a cellular mechanism for the previously reported role of NMDA receptors in opiate tolerance and dependence.
伏隔核（NAcc）可能在阿片类药物依赖中起主要作用，据报道中枢N-甲基-D-天冬氨酸（NMDA）受体可影响阿片类药物耐受性和依赖性。因此，我们使用脑片制备中的细胞内记录方法，研究了选择性μ-阿片受体激动剂[D-丙氨酸2-N-甲基苯丙氨酸4，甘醇5]-脑啡肽（DAMGO）对大鼠伏隔核神经元膜特性以及由NMDA和非NMDA谷氨酸受体介导的事件的影响。大多数伏隔核神经元在超极化时表现出明显的内向整流（与对Cs +和Ba2 +敏感的内向松弛相关），以及正电流脉冲引起的缓慢去极化斜坡。灌注DAMGO不会改变膜电位、输入电阻或内向松弛。在使用6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）阻断非NMDA谷氨酸受体和荷包牡丹碱阻断GABAA受体的情况下，局部刺激诱发的兴奋性突触后电位（EPSP）表现出NMDA成分的特征：（1）持续时间长，（2）电压敏感性，以及（3）被NMDA受体拮抗剂DL-2-氨基-5-磷酸戊酸（D-APV）阻断。DAMGO（0.1 - 1μM）显著降低NMDA和非NMDA-EPSP幅度，纳洛酮和μ-选择性拮抗剂[半胱氨酸2-酪氨酸3-鸟氨酸5-喷他肽7]-生长抑素酰胺（CTOP）可逆转此效应。为了评估DAMGO的突触后作用，我们用河豚毒素灌注脑片并通过局部应用谷氨酸激动剂诱发内向电流。令人惊讶的是，0.1 - 1μM DAMGO显著增强NMDA电流（CTOP可逆转），但降低非NMDA电流。在较高浓度（5μM）时，DAMGO降低NMDA电流，但CTOP增强而非阻断此效应。这些结果表明DAMGO对伏隔核中谷氨酸能突触传递的NMDA成分具有复杂的调节作用：μ受体激活在突触前降低NMDA-EPSP幅度，但在突触后增加NMDA电流。这些新数据可能为先前报道的NMDA受体在阿片类药物耐受性和依赖性中的作用提供细胞机制。
