Migraine is a pain disorder that affects 10 – 15% of the population worldwide. Even though there is a wide choice of therapeutics that includes different classes of well-tolerated drugs, numerous patients are still not satisfied with their treatment. Trigeminal ganglion and nucleus caudalis are enriched with nociceptin/orphanin FQ (N/OFQ) receptor (NOP)-expressing cells. The general aim of the present study is to investigate the role of the N/OFQ – NOP system in the modulation of migraine. This study evaluated the phenotype of mice with genetically induced knockout of the NOP receptor gene (NOP(-/-)) in two migraine models, namely, migraine induced by intraperitoneal injection of GTN, and migraine induced by intraperitoneal injection of CGRP. Additionally, the efficacy of a small-molecule NOP receptor agonist AT-403 in the prevention of periorbital mechanical allodynia triggered by CGRP has been tested.NOP(+/+) and NOP(-/-) male and female mice were used. To assess the periorbital mechanical allodynia (PMA) as a measure of migraine pain Von Frey filaments have been used. Nitroglycerin (GTN) or CGRP were used as migraine triggers.Both male and female NOP(-/-) mice displayed higher sensitivity than NOP(+/+) mice to the GTN effects. No major genotype effects were recorded using CGRP as a migraine trigger. The NOP receptor agonist AT-403 dose-dependently counteracts CGRP-induced PMA in male and female mice.Collectively these results corroborate the premise that the NOP receptor may be a promising therapeutic target for the development of innovative drugs for anti-migraine treatment.