NOP receptor activation counteracts stress-induced migraine-like behaviors in mice

Stress is a major trigger of migraine, yet the underlying mechanisms remain unclear. Previous evidence supports the nociceptin/orphanin FQ (N/OFQ)/NOP receptor system as a potential target for novel anti-migraine strategies, although its role in stress-induced and persistent migraine-like states remains unclear. We evaluated the role of the N/OFQ/NOP receptor system in a mouse model where repeated restraint stress induces periorbital mechanical allodynia (PMA) and primes responses to a subthreshold dose of nitroglycerin (GTN, 0.1 mg/kg). Experiments were performed in male mice, as a first study showed that stress did not sensitize females to subthreshold GTN under our conditions. Stress-induced PMA resolved in young mice but persisted for weeks in older animals, inducing a persistent migraine-like phenotype. GTN, inactive in naïve mice, evoked PMA only in previously stressed animals. NOP knockout did not alter animal susceptibility, whereas NOP stimulation with the brain-penetrant NOP agonist AT-403 (30 μg/kg) or the peripherally restricted agonist UFP-112 (10 pmol) prevented GTN-evoked PMA and reversed stress-induced PMA, including persistent allodynia in older adult mice. Comparable efficacy of UFP-112 and AT-403 supports the contribution of peripheral NOP receptors. Together, our findings expand the evidence beyond acute pharmacological models, supporting the potential of NOP agonists for the treatment of both acute and persistent migraine.