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

Abstract

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.