A non‐convulsant delta‐opioid receptor agonist, KNT‐127, reduces cortical spreading depression and nitroglycerin‐induced allodynia

OBJECTIVE: The aim of this study was to determine if the non-convulsant delta opioid receptor agonist, KNT-127, could inhibit migraine-associated endpoints. BACKGROUND: The delta opioid receptor has been identified as a therapeutic target for migraine. However, development of delta agonists is limited as some ligands have seizurogenic properties, which may be related to their ability to induce receptor internalization. While both pro- and non-convulsant delta agonists can reduce migraine associated allodynia, only the pro-convulsant agonist, SNC80, has been shown to decrease cortical spreading depression. It is unclear if the ability of delta agonists to modulate cortical activity is related to the same signaling mechanisms that produce pro-convulsant effects. METHODS: The effects of the non-convulsant delta agonist, KNT-127, were examined. Repetitive cortical spreading depression was induced in female C57BL6/J (n=6/group) mice by continuous application of KCl; and the effect of KNT-127/vehicle on both local field potentials and optical intrinsic signals was determined. To assess the effect of KNT-127 on established chronic migraine-associated pain, male and female C57BL6/J mice were treated with nitroglycerin (10 mg/kg, IP) every other day for 9 days; and tested with KNT-127 (5 mg/kg SC) or vehicle on day 10 (n=6/group). DOR-eGFP mice (n=4/group) were used to confirm the internalization properties of KNT-127 in the trigeminal ganglia, trigeminal nucleus caudalis, and the somatosensory cortex. RESULTS: KNT-127 inhibited cortical spreading depression events (t((10))=3.570, p=0.0051). In addition, this delta agonist also reversed established cephalic allodynia in the nitroglycerin model of chronic migraine (F((1, 20)) = 12.80, p