Vasodilator responses to the endomorphin peptides, but not nociceptin/OFQ, are mediated by nitric oxide release

The endomorphin peptides, endogenous ligands for the μ-opioid receptor, and nociceptin (orphanin FQ; OFQ), an endogenous ligand for the ORL₁ receptor, have substantial vasodilator activity in the rat. The roles of nitric oxide, vasodilator prostaglandins, and the opening of K⁺(ATP) channels in mediating vasodilator responses to these novel agonists were investigated in the hindquarters vascular bed of the rat. Under constant-flow conditions, injections of the μ-selective agonists, endomorphin 1 and 2, PL017 ([N-MePhe³, D-Pro⁴]-morphiceptin), and DAMGO, and the ORL₁ receptor agonist, nociceptin/OFQ, produced dose-dependent decreases in hindquarters perfusion pressure. Vasodilator responses to endomorphin 1, PL017, and DAMGO were attenuated by the nitric oxide synthase inhibitor L-NAME at a time when vasodilator responses to nociceptin/OFQ were not altered. Responses to endomorphin 1 and 2, PL017, DAMGO, and nociceptin/OFQ were not altered by the cyclooxygenase inhibitor sodium meclofenamate or the K⁺(ATP) channel blocker U-37883A. The results of these studies indicate that responses to endomorphin 1 and 2, PL017, and DAMGO are mediated in large part by the release of nitric oxide, while responses to nociceptin/OFQ are mediated by an L-NAME-insensitive mechanism. Moreover, these results demonstrate that responses to these peptides are not mediated by the release of vasodilator prostaglandins or K⁺(ATP) channel opening in the hindquarters vascular bed.