Nociceptin/orphanin FQ dilates pial arteries by K(ATP) and K(ca) channel activation.

Nociceptin/orphanin FQ (NOC/oFQ) is a recently discovered endogenous ligand for the opioid like receptor, ORL-1. In the piglet, cGMP activates the ATP sensitive (K(ATP)) while cAMP activates both the K(ATP) and the calcium sensitive (K(ca)) K(+) channel to elicit vasodilation. The present study was designed to characterize the role of cGMP, cAMP, K(ATP), and K(ca) channel activation in NOC/oFQ-induced pial artery dilation in newborn pigs equipped with a closed cranial window. NOC/oFQ (10(-8), 10(-6) M) induced pial arteriole dilation was decreased by the protein kinase A inhibitor Rp 8-Br cAMPs (16+/-1 and 30+/-1 vs. 5+/-1 and 10+/-1%). NOC/oFQ dilation was associated with elevated CSF cAMP (1037+/-58 vs. 1919+/-209 fmol/ml for control and 10(-6) M NOC/oFQ). Glibenclamide and iberiotoxin, K(ATP) and K(ca) channel antagonists, attenuated NOC/oFQ induced dilation (15+/-1 and 28+/-1 vs. 10+/-1 and 19+/-1% before and after iberiotoxin). In contrast, the nitric oxide synthase inhibitor, L-NNA, and the protein kinase G inhibitor, Rp 8-Br cGMPs had no effect on NOC/oFQ dilation while such dilation was not associated with a change in CSF cGMP. The putative ORL-1 receptor antagonist [F/G] NOC/oFQ (1-13)-NH(2) blocked NOC/oFQ dilation while responses were unchanged after naloxone (17+/-1 and 30+/-2 vs. 3+/-1 and 5+/-1%, before and after [F/G] NOC/oFQ (1-13)-NH(2)). Dilation to other opioids (e.g., methionine enkephalin) was unchanged by [F/G] NOC/oFQ (1-13)-NH(2). These data show that NOC/oFQ elicits pial artery dilation, at least in part, via cAMP, K(ATP), and K(ca) channel dependent mechanisms. These data suggest that such a mechanism involves the sequential release of cAMP and subsequent K(ATP) and K(ca) channel activation.