Bonanno G, Fassio A, Sala R, Schmid G, Raiteri M
Department of Experimental Medicine, University of Genova, Italy.
Eur J Pharmacol. 1998 Dec 4;362(2-3):143-8. doi: 10.1016/s0014-2999(98)00759-6.
The effects of GABA(B) receptor activation on the Ca2+-dependent depolarization-induced overflow of endogenous glutamic acid and gamma-aminobutyric acid (GABA) was studied in rat spinal cord nerve terminals exposed in superfusion to 15 mM KCl. The GABA(B) receptor agonist (-)-baclofen inhibited the K+-evoked overflow of glutamate (EC50=0.098 microM) but was almost inactive against that of GABA. The overflow of both transmitters could be quite similarly inhibited by two other GABA(B) receptor agonists, 3-APPA (3-aminopropylphosphonous acid; EC50=0.087 and 0.050 microM in the case of GABA and glutamate, respectively) and CGP 44532 (3-amino-2(S)-hydroxypropyl)methylphosphinic acid; EC50=0.81 and 0.50 microM). The GABA(B) receptor antagonist CGP 35348 [3-amino-propyl(diethoxymethyl)phosphinic acid] blocked the effect of 3-APPA (1 microM) at the autoreceptors (IC50 approximately = 1 microM), but not at the heteroreceptors. In contrast, the effects of 3-APPA at both autoreceptors and heteroreceptors could be similarly prevented by another GABA(B) receptor antagonist, CGP 52432 [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl) phosphinic acid (IC50 approximately = 10 microM). The data suggest that, in the spinal cord, GABA(B) autoreceptors on GABA-releasing terminals differ pharmacologically from GABA(B) heteroreceptors on glutamatergic terminals. Selective GABA(B) receptor ligands may be helpful for conditions characterized by excessive glutamatergic transmission in the spinal cord.
在经15 mM氯化钾灌流的大鼠脊髓神经末梢中，研究了GABA(B)受体激活对内源性谷氨酸和γ-氨基丁酸（GABA）的Ca2+依赖性去极化诱导释放的影响。GABA(B)受体激动剂(-)-巴氯芬抑制K+诱发的谷氨酸释放（EC50 = 0.098 microM），但对GABA释放几乎无作用。另外两种GABA(B)受体激动剂3-APPA（3-氨基丙基膦酸；GABA和谷氨酸的EC50分别为0.087和0.050 microM）和CGP 44532（3-氨基-2(S)-羟丙基）甲基次膦酸；EC50 = 0.81和0.50 microM）对两种递质的释放抑制作用相当相似。GABA(B)受体拮抗剂CGP 35348 [3-氨基丙基（二乙氧基甲基）次膦酸]在自身受体处阻断3-APPA（1 microM）的作用（IC50约 = 1 microM），但在异源受体处无此作用。相反，另一种GABA(B)受体拮抗剂CGP 52432 [3-[[(3,4-二氯苯基)甲基]氨基]丙基]（二乙氧基甲基）次膦酸（IC50约 = 10 microM）可同样阻断3-APPA在自身受体和异源受体处的作用。数据表明，在脊髓中，GABA释放末梢上的GABA(B)自身受体在药理学上与谷氨酸能末梢上的GABA(B)异源受体不同。选择性GABA(B)受体配体可能有助于治疗脊髓中谷氨酸能传递过度的病症。
