Influence of cAMP on cerebrospinal fluid opioid concentration: role in cAMP-induced pial artery dilation

Abstract

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.