Acetyl-RYYRIK-NH2 is a highly efficacious OP4 receptor agonist in the cardiovascular system of anesthetized rats

Nociceptin, the endogenous ligand of the OF4 or ORL1 (opioid receptor-like, ) receptor, decreases blood pressure and heart rare in anesthetized rats, S ince the OP4 receptor antagonist [Phe(1)Psi (CH2-NH)Gly(2)]-nociceptin(1-13 )NH2 possesses an agonistic effect in this model, we examined whether other purported OP4 receptor antagonists, acetyl-RYYRIK-NH2 and naloxone benzoyl hydrazone, antagonize the depressant effects of nociceptin. Acetyl-RYYRIK-N H2, like nociceptin and [Phe(1)Psi (CH2-NH)Gly(2)]-nociceptin(1-13)NH2 and unlike naloxone benzoylhydrazone, decreased diastolic blood pressure and he art rate (rank order of potencies: nociceptin approximate to acetyl-RYYRIK- NH2 much greater than [Phe(1)Psi (CH2-NH)Gly(2)]-nociceptin(1-13)NH2). The depressant effects were insensitive to the OP1-3 receptor antagonist naloxo ne but diminished by naloxone benzoylhydrazone. In conclusion, the hypotens ive and bradycardic effects of nociceptin in the anesthetized rat are media ted via OP4 receptors, at which acetyl-RYYRIK-NH2 is a highly potent and ef ficacious agonist. (C) 2000 Elsevier Science Inc. All rights reserved.