Wilderman M J, Armstead W M
Department of Anesthesia, University of Pennsylvania, Philadelphia, USA.
Eur J Pharmacol. 1996 Aug 15;309(3):243-9. doi: 10.1016/0014-2999(96)00348-2.
Previously, it has been observed that cGMP analogs and agents that elevate cGMP levels markedly increase the concentration of the opioids [Met5]enkephalin and [Leu5]enkephalin in cortical periarachnoid cerebrospinal fluid (CSF) of the newborn pig. However, such agents had no effect on CSF dynorphin-(1-13) concentration. The present study was designed to: (1) investigate the influence of cAMP on the CSF concentration of the opioids [Met5]enkephalin, [Leu5]enkephalin and dynorphin-(1-13); and (2) determine the role of these opioids in cAMP-induced pial artery vasodilation. Piglets equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid CSF for assay of opioids. The cAMP analog, 8-Bromoadenosine-3',5'-cyclic monophosphate (8-Bromo cAMP) elicited pial dilation that was blunted by a cAMP antagonist, Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate (10(-5) M) (11 +/- 1 and 19 +/- 1 vs. 1 +/- 1 and 1 +/- 1 for 10(-8) M, 10(-6) M 8-Bromo cAMP before and after Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate, respectively). The dilation produced by 8-Bromo cAMP was accompanied by modest increases in CSF [Met5]enkephalin and co-administration of Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate with 8-Bromo cAMP blocked these increases in CSF opioid concentration (1179 +/- 48, 1593 +/- 92 and 2079 +/- 88 vs. 1054 +/- 32, 1038 +/- 15 and 1071 +/- 17 pg/ml for control, 10(-8) M and 10(-6) M 8-Bromo cAMP before and after Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate, respectively). The release of CSF [Leu5]enkephalin by 8-Bromo cAMP was also blocked by Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate. In contrast 8-Bromo cAMP produced marked increases in CSF dynorphin-(1-13) (38 +/- 3, 61 +/- 3 and 88 +/- 6 vs. 27 +/- 3, 28 +/- 3 and 30 +/- 4 pg/ml for control, 10(-8) M and 10(-6) M 8-Bromo cAMP before and after Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate, respectively). Similar blunted vascular and biochemical responses were observed with the co-administration of Sp 8-Bromoadenosine-3',5'-cyclic monophosphorothioate, another analog of cAMP, with Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate. The opioid receptor antagonist naloxone (1 mg/kg i.v.) attenuated 8-Bromo cAMP-induced dilation (9 +/- 1 and 17 +/- 1 vs. 5 +/- 1 and 8 +/- 1 for 10(-8) M, 10(-6) M 8-Bromo cAMP before and after naloxone). These data show that cAMP contributes to the release of the CSF opioids [Met5]enkephalin, [Leu5]enkephalin and dynorphin-(1-13), and suggest that, while cGMP is more important relative to cAMP in elevating CSF [Met5]enkephalin and [Leu5]enkephalin concentration, the converse is true for dynorphin-(1-13). Further, these data indicate that opioids contribute to cAMP-induced pial artery vasodilation.
此前观察到，环鸟苷酸（cGMP）类似物及能提高cGMP水平的药物可显著增加新生仔猪皮质蛛网膜下腔脑脊液（CSF）中阿片类物质[Met5]脑啡肽和[Leu5]脑啡肽的浓度。然而，此类药物对CSF中强啡肽-（1 - 13）的浓度并无影响。本研究旨在：（1）研究环磷酸腺苷（cAMP）对CSF中阿片类物质[Met5]脑啡肽、[Leu5]脑啡肽和强啡肽-（1 - 13）浓度的影响；（2）确定这些阿片类物质在cAMP诱导的软脑膜动脉血管舒张中的作用。配备封闭颅窗的仔猪用于测量软脑膜动脉直径，并收集皮质蛛网膜下腔CSF以检测阿片类物质。cAMP类似物8 - 溴腺苷 - 3',5'-环一磷酸（8 - 溴cAMP）引起软脑膜舒张，该舒张作用被cAMP拮抗剂Rp 8 - 溴腺苷 - 3',5'-环硫代磷酸酯（10(-5) M）减弱（10(-8) M、10(-6) M 8 - 溴cAMP在Rp 8 - 溴腺苷 - 3',5'-环硫代磷酸酯处理前后，软脑膜动脉直径分别为11 ± 1和19 ± 1，以及1 ± 1和1 ± 1）。8 - 溴cAMP引起的舒张伴随着CSF中[Met5]脑啡肽适度增加，Rp 8 - 溴腺苷 - 3',5'-环硫代磷酸酯与8 - 溴cAMP共同给药可阻断CSF中阿片类物质浓度的这些增加（对照、10(-8) M和10(-6) M 8 - 溴cAMP在Rp 8 - 溴腺苷 - 3',5'-环硫代磷酸酯处理前后，CSF中阿片类物质浓度分别为1179 ± 48、1593 ± 92和2079 ± 88，以及1054 ± 32、1038 ± 15和1071 ± 17 pg/ml）。Rp 8 - 溴腺苷 - 3',5'-环硫代磷酸酯也可阻断8 - 溴cAMP诱导的CSF中[Leu5]脑啡肽释放。相反，8 - 溴cAMP使CSF中强啡肽-（1 - 13）显著增加（对照、10(-8) M和10(-6) M 8 - 溴cAMP在Rp 8 - 溴腺苷 - 3',5'-环硫代磷酸酯处理前后，CSF中强啡肽-（1 - 13）浓度分别为38 ± 3、61 ± 3和88 ± 6，以及27 ± 3、28 ± 3和30 ± 4 pg/ml）。cAMP的另一种类似物Sp 8 - 溴腺苷 - 3',5'-环硫代磷酸酯与Rp 8 - 溴腺苷 - 3',5'-环硫代磷酸酯共同给药时，观察到类似的血管和生化反应减弱。阿片受体拮抗剂纳洛酮（1 mg/kg静脉注射）减弱了8 - 溴cAMP诱导的舒张（10(-8) M、10(-6) M 8 - 溴cAMP在纳洛酮处理前后，软脑膜动脉直径分别为9 ± 1和17 ± 1，以及5 ± 1和8 ± 1）。这些数据表明，cAMP有助于CSF中阿片类物质[Met5]脑啡肽、[Leu5]脑啡肽和强啡肽-（1 - 13）的释放，并表明，虽然相对于cAMP，cGMP在提高CSF中[Met5]脑啡肽和[Leu5]脑啡肽浓度方面更重要，但对强啡肽-（1 - 13）而言则相反。此外，这些数据表明阿片类物质有助于cAMP诱导的软脑膜动脉血管舒张。
