INFLUENCE OF CAMP ON CEREBROSPINAL-FLUID OPIOID CONCENTRATION - ROLE IN CAMP-INDUCED PIAL ARTERY DILATION

Previously, it has been observed that cCMP analogs and agents that ele vate cGMP levels markedly increase the concentration of the opioids [M et(5)]enkephalin and [Leu(5)]enkephalin in cortical periarachnoid cere brospinal fluid (CSF) of the newborn pig. However, such agents had no effect on CSF dynorphin-(1-13) concentration. The present study was de signed to: (1) investigate the influence of cAMP on the CSF concentrat ion of the opioids [Met(5)]enkephalin, [Leu(5)]enkephalin and dynorphi n-(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 periar achnoid CSF for assay of opioids. The cAMP analog, 8-Bromoadenosine-3' ,5'-cyclic monophosphate (8-Bromo cAMP) elicited pial dilation that wa s blunted by a cAMP antagonist, Rp 8-Bromoadenosine-3',5'-cyclic monos phorothioate (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-Bromoadenos ine-3',5'-cyclic monosphorothioate, respectively). The dilation produc ed by 8-Bromo cAMP was accompanied by modest increases in CSF [Met(5)] enkephalin and co-administration of Rp 8-Bromoadenosine-3',5'-cyclic m onosphorothioate with 8-Bromo cAMP blocked these increases in CSF opio id 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 mo nosphorothioate, respectively). The release of CSF [Leu(5)]enkephalin by 8-Bromo cAMP was also blocked by Rp 8-Bromoadenosine-3',5'-cyclic m onosphorothioate. 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-Brom o cAMP before and after Rp 8-Bromoadenosine-3',5'-cyclic monosphorothi oate, respectively). Similar blunted vascular and biochemical response s were observed with the co-administration of Sp 8-Bromoadenosine-3'5' -cyclic monophosphorothioate, another analog of cAMP, with Rp 8-Bromoa denosine-3',5'-cyclic monosphorothioate. The opioid receptor antagonis t 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-Br omo cAMP before and after naloxone). These data show that cAMP contrib utes to the release of the CSF opioids [Met(5)]enkephalin, [Leu(5)]enk ephalin and dynorphin-(1-13), and suggest that, while cGMP is more imp ortant relative to cAMP in elevating CSF [Met(5)]enkephalin and [Leu(5 )]enkephalin concentration, the converse is true for dynorphin-(1-13). Further, these data indicate that opioids contribute to cAMP-induced pial artery vasodilation.