Ro 64-6198, a selective NOP receptor agonist attenuates social impairments associated with NTG-induced migraine pain

Migraine is a debilitating neurological disorder with significant impact on quality of life, including social functioning. This study investigated the effects of nitroglycerin (NTG)-induced migraine in male and female mice on social behavior and neuronal activation and explored the therapeutic potential of nociceptin opioid peptide (NOP) receptor agonism. We found that acute NTG administration induced mechanical allodynia in periorbital region and paw as well as impaired social behavior in both sexes, albeit with sex-specific patterns. The NOP receptor agonist, Ro 64-6198, reversed both the allodynia and social deficits induced by NTG. The reversal of social impairment elicited by Ro 64-6198 was partially blocked by the NOP receptor antagonist, SB-612111, confirming NOP receptor-mediated action. Using TRAP2/Ai9 transgenic mice, we demonstrated that NTG induced significant neuronal activation in brain regions associated with pain and social behavior, including the anterior cingulate cortex, amygdala, hippocampus, hypothalamus, and periaqueductal gray (in female mice) as well as trigeminal nucleus caudalis (TNC) in male and female mice. Consistent with the behavioral results, NTG-induced neuronal activation in these brain regions was significantly reduced in the presence of Ro 64-6198. Our findings provide further evidence for the involvement of the NOP system in migraine pathophysiology, particularly social aspects that are indirectly pain related symptoms, and provide a direct correlation with neuronal activation in several brain regions.