Marabese Ida, de Novellis Vito, Palazzo Enza, Mariani Loredana, Siniscalco Dario, Rodella Luigi, Rossi Francesco, Maione Sabatino
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Faculty of Medicine and Surgery, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
Neuropharmacology. 2005;49 Suppl 1:157-66. doi: 10.1016/j.neuropharm.2005.02.006. Epub 2005 Apr 1.
We investigated the role of group III metabotropic glutamate (mGlu) receptors on glutamate and GABA releases at the periaqueductal grey (PAG) level by using in vivo microdialysis in rats. Intra-PAG perfusion of either L-(+)-2-amino-4-phosphonobutyric acid (L-AP4, 100-300 microM), (RS)-4-phosphonophenylglycine ((RS)-PPG, 100-300 microM) selective agonists of group III mGlu receptors, or (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG, 50-100 microM), a selective agonist of mGlu8 receptor, increased glutamate and decreased GABA extracellular concentrations. (RS)-alpha-methylserine-O-phosphate (MSOP, 0.5 mM), a selective group III receptor antagonist, perfused in combination with (S)-3,4-DCPG, L-AP4 or (RS)-PPG, antagonised the effects induced by these agonists on both extracellular glutamate and GABA values. alpha-Methyl-3-methyl-4-phosphonophenylglycine (UBP1112, 300 microM), a group III mGlu receptor antagonist, perfused in combination with (RS)-PPG or (S)-3,4-DCPG, antagonised the effects induced by these agonists. Intra-PAG perfusion with forskolin (100 microM), an activator of adenylate cyclase, increased dialysate glutamate and GABA levels. Moreover, intra-PAG perfusion with N-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89) (100 microM), a protein kinase (PKA) inhibitor, abolished the effect of (S)-3,4-DCPG on both glutamate and GABA releases. H-89, per se, did not modify glutamate release but reduced extracellular GABA value at the higher dosage used (200 microM). These data suggest that group III mGlu receptors in the PAG modulate the releases of glutamate and GABA conversely. In particular, both the facilitation of glutamate and the inhibition of GABA releases require the participation of coupling to adenylate cyclase and the subsequent activation of the PKA pathway.
我们通过在大鼠体内进行微透析，研究了Ⅲ型代谢型谷氨酸（mGlu）受体在导水管周围灰质（PAG）水平对谷氨酸和γ-氨基丁酸（GABA）释放的作用。向PAG内灌注Ⅲ型mGlu受体的选择性激动剂L-(+)-2-氨基-4-膦酰丁酸（L-AP4，100 - 300微摩尔）、(RS)-4-膦酰苯甘氨酸（(RS)-PPG，100 - 300微摩尔）或mGlu8受体的选择性激动剂(S)-3,4-二羧基苯甘氨酸（(S)-3,4-DCPG，50 - 100微摩尔），可增加谷氨酸并降低细胞外GABA浓度。与(S)-3,4-DCPG、L-AP4或(RS)-PPG联合灌注选择性Ⅲ型受体拮抗剂(RS)-α-甲基丝氨酸-O-磷酸（MSOP，0.5毫摩尔），可拮抗这些激动剂对细胞外谷氨酸和GABA值的影响。Ⅲ型mGlu受体拮抗剂α-甲基-3-甲基-4-膦酰苯甘氨酸（UBP1112，300微摩尔）与(RS)-PPG或(S)-3,4-DCPG联合灌注，可拮抗这些激动剂的作用。向PAG内灌注腺苷酸环化酶激活剂福斯高林（100微摩尔），可增加透析液中谷氨酸和GABA水平。此外，向PAG内灌注蛋白激酶（PKA）抑制剂N-[2-(对溴肉桂基氨基)乙基]-5-异喹啉磺酰胺二盐酸盐（H-89）（100微摩尔），可消除(S)-3,4-DCPG对谷氨酸和GABA释放的影响。H-89本身不改变谷氨酸释放，但在较高剂量（200微摩尔）时可降低细胞外GABA值。这些数据表明，PAG中的Ⅲ型mGlu受体对谷氨酸和GABA的释放起相反的调节作用。特别是，谷氨酸的促进作用和GABA释放的抑制作用都需要与腺苷酸环化酶偶联并随后激活PKA途径的参与。
