Analysis of Vasodepressor Responses to Nociceptin and Nociceptin Analogs in the Systemic Vascular Bed of the Anesthetized Rabbit In Vivo

Background: The heptadecapeptide nociceptin, also known as Orphanin FQ, is a recently discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL(1). Methods and Results: In the present study, responses to nociceptin, [Tyr(1)]-nociceptin, nociceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) were compared in the systemic vascular bed of the rabbit. Nociceptin and [Tyr(1)]-nociceptin induced dose related decreases in systemic arterial pressure (SAP) when injected in doses of 1-30 nmol/kg intravenous (IV); in terms of relative vasodepressor activity, [Tyr(1)]-nociceptin and nocicpetin were similar in potency. However, nocicpetin-(2-17), nocicpetin-(1-11), and nociceptin-(1-7) had no effect on SAP when injected in doses up to 30 nmol/kg IV. The decreases in SAP in response to nociceptin and [Tyr(1)]-nociceptin were not altered by the opioid receptor antagonist naloxone at a time when depressor responses to methionine-enkephalin were reduced significantly. Conclusions: The results of the present study show that vasodepressor responses to nociceptin and [Tyr(1)]-nocicpetin are mediated by the activation of a naloxene-insensitive opioid receptor and are not dependent on the presence of Phe at the N-terminus of the nociceptin sequence. Moreover, the present results show that nociceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) do not alter SAP in the rabbit, indicating that peptide chain length is important for the expression of vasodepressor activity.