Lupica C R, Proctor W R, Dunwiddie T V
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
Brain Res. 1992 Oct 16;593(2):226-38. doi: 10.1016/0006-8993(92)91312-3.
Modulation of gamma-aminobutyric acid (GABA)-mediated inhibition, and glutamate-mediated excitation by highly selective mu and delta opioid agonists was studied using intracellular recordings of CA1 pyramidal neuron synaptic responses in superfused hippocampal slices. Equimolar concentrations of the selective mu agonist, [Tyr-(D-Ala)-Gly-(N-Me-Phe)-Gly-ol]-enkephalin (DAGO), or the delta selective agonist, [D-Pen2,D-Pen5]-enkephalin (DPDPE), reversibly increased the amplitudes of excitatory post-synaptic potentials (EPSPs), evoked by Schaffer collateral/commissural stimulation, without altering the input resistance or resting membrane potential of these CA1 pyramidal neurons. The increased EPSP amplitudes resulting from superfusion with the enkephalin analogs were qualitatively similar to those caused by the GABAA receptor antagonist, bicuculline methiodide (BMI). Specific stimulation/recording protocols and micro-lesions of the slices were used to evoke relatively pure forms of recurrent and feed-forward GABA-mediated inhibitory post-synaptic potentials (IPSPs). The mu opioid agonist DAGO reduced both recurrent and feed-forward IPSPs, while the delta agonist DPDPE had no effect upon these responses. To test the hypothesis that the enhancement of pyramidal neuron EPSPs by delta (and mu) opioids was due to the reduction of an inhibitory potential that was coincident with the EPSP, DPDPE or the mu agonist, DAGO, were applied while recording monosynaptic IPSPs following the elimination of EPSPs by the glutamate receptor antagonists, D,L-2-amino-5-phosphonovalerate (APV) and 6,7-dinitroquinoxaline-2,3-dione (DNQX). The mu agonist, DAGO, reversibly reduced these pharmacologically isolated IPSPs, while the delta agonist, DPDPE, had no effect upon these responses. Despite the fact that the delta agonist, DPDPE, had no effect on recurrent, feed-forward or monosynaptic evoked IPSPs, this enkephalin did reversibly reduce the frequency of spontaneously occurring IPSPs, measured using whole-cell recordings with pipettes containing 65 mM KCl. The mu agonist, DAGO, and the GABAA antagonist, BMI, similarly reduced spontaneous IPSP rates. We conclude from these data that mu and delta opioid receptor activation increases EPSPs via the reduction of a form of GABAergic inhibition that is difficult to characterize, and which may be distinct from conventional feed-forward and recurrent inhibition. Furthermore, delta opioids seem to reduce this form of GABAergic inhibition selectively, while mu opioids reduced this inhibition, and conventional feed-forward and recurrent IPSPs as well.
使用海马脑片细胞内记录技术，研究了高选择性μ和δ阿片类激动剂对γ-氨基丁酸（GABA）介导的抑制作用以及谷氨酸介导的兴奋作用的调节。选择性μ激动剂[酪氨酸-（D-丙氨酸）-甘氨酸-（N-甲基苯丙氨酸）-甘氨酸-醇]-脑啡肽（DAGO）或δ选择性激动剂[D-青霉胺2，D-青霉胺5]-脑啡肽（DPDPE）的等摩尔浓度，可逆地增加了由Schaffer侧支/连合刺激诱发的兴奋性突触后电位（EPSP）的幅度，而不改变这些CA1锥体神经元的输入电阻或静息膜电位。用脑啡肽类似物灌流导致的EPSP幅度增加，在性质上与GABAA受体拮抗剂甲硫双环丙酯（BMI）引起的增加相似。使用特定的刺激/记录方案和脑片微损伤来诱发相对纯粹形式的回返性和前馈性GABA介导的抑制性突触后电位（IPSP）。μ阿片类激动剂DAGO降低了回返性和前馈性IPSP，而δ激动剂DPDPE对这些反应没有影响。为了检验δ（和μ）阿片类药物增强锥体神经元EPSP是由于减少了与EPSP同时出现的抑制性电位这一假说，在使用谷氨酸受体拮抗剂D，L-2-氨基-5-磷酸戊酸（APV）和6，7-二硝基喹喔啉-2，3-二酮（DNQX）消除EPSP后，记录单突触IPSP时应用DPDPE或μ激动剂DAGO。μ激动剂DAGO可逆地降低了这些药理学分离的IPSP，而δ激动剂DPDPE对这些反应没有影响。尽管δ激动剂DPDPE对回返性、前馈性或单突触诱发的IPSP没有影响，但这种脑啡肽确实可逆地降低了使用含65 mM KCl的移液管进行全细胞记录测量的自发性IPSP的频率。μ激动剂DAGO和GABAA拮抗剂BMI同样降低了自发性IPSP频率。从这些数据我们得出结论，μ和δ阿片受体激活通过减少一种难以表征的GABA能抑制形式来增加EPSP，这种抑制形式可能与传统的前馈性和回返性抑制不同。此外，δ阿片类药物似乎选择性地减少这种GABA能抑制形式，而μ阿片类药物则减少这种抑制以及传统的前馈性和回返性IPSP。
