ROLE OF PACAP IN THE RELATIONSHIP BETWEEN CAMP AND OPIOIDS IN HYPOXIA-INDUCED PIAL ARTERY VASODILATION

The opioids methionine enkephalin and leucine enkephalin contribute to hypoxic pial artery dilation in the newborn pig, and adenosine 3',5'- cyclic monophosphate (cAMP) analogs have been shown to elevate cerebro spinal fluid (CSF) opioid concentration. The present study was designe d to investigate the contribution of cAMP to hypoxic dilation and to d etermine whether an endogenous activator of adenylate cyclase, pituita ry adenyl ate cyclase-activating peptide (PACAP), could modulate the c AMP-induced release of opioids to contribute to hypoxic pial dilation in piglets equipped with closed cranial windows. An cr level of P < 0. 05 was considered significant in all statistical tests. Moderate and s evere hypoxia (PO2 approximate to 35 and 25 mmHg, respectively) induce d pial artery dilation that was attenuated by the Rp diastereomer of 8 -bromoadenosine 3',5'-cyclic monophosphothioate (Rp-8-BrcAMPS), a cAMP antagonist (24 +/- 1 and 36 +/- 2% vs. 21 +/- 1 and 30 +/- 1% for mod erate hypoxia and 34 +/- 1 and 46 +/- 2% vs. 24 +/- 1 and 32 +/- 1% fo r severe hypoxia before and after Rp-8-BrcAMPS, respectively). These r esponses were associated with an increased CSF cAMP (1,046 +/- 25, 1,3 66 +/- 28, and 1,735 +/- 47 fmol/ml for control, moderate, and severe hypoxia, respectively). Hypoxic pial dilation was also accompanied by an increase in CSF methionine enkephalin (1,101 +/- 62, 3,283 +/- 119, and 3,835 +/- 129 pg/ml for control, moderate, and severe hypoxia, re spectively). Hypoxic dilation additionally increased CSF PACAP (1,727 +/- 86, 2,268 +/- 157, and 7,980 +/- 238 pg/ml for control, moderate, and severe hypoxia, respectively). PACAP (10(-8) and 10(-6) M) elicite d pial dilation that was associated with increased CSF cAMP and blunte d by Rp-8-BrcAMPS. PACAP-induced dilation was also accompanied by incr eases in the opioid methionine enkephalin (1,059 +/- 23, 1,483 +/- 34, and 2,108 +/- 77 pg/ml for control and 10(-8) and 10(-6) M PACAP, res pectively). These data show that cAMP contributes to hypoxic pial arte ry dilation. Hypoxia increases CSF PACAP, whereas PACAP elevates CSF o pioid concentration. These data, therefore, suggest that PACAP modulat es cAMP-induced opioid release, thereby contributing to hypoxic pial d ilation.