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.
Departments of Anesthesia and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Armstead
D000818:Animals; D000831:Animals, Newborn; D002536:Cerebral Arteries / Q000187:drug effects*; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D005260:Female; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D018847:Opioid Peptides / Q000494:pharmacology*; D010841:Pia Mater / Q000098:blood supply / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects*; D011957:Receptors, Opioid / Q000819:agonists*; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*; D000097629:Nociceptin
D000242:Cyclic AMP; D006152:Cyclic GMP; D009569:Nitric Oxide; D018847:Opioid Peptides; D015221:Potassium Channels; D011957:Receptors, Opioid; D014665:Vasodilator Agents; D000097629:Nociceptin