Vasopressin 1A and 1B receptor-mediated antinociception in a mouse model of cortical spreading depolarization

The purpose of this study is to elucidate the role of vasopressin 1 receptors (V1Rs) in migraine with aura. Cortical spreading depolarization (SD) is a slow depolarizing wave that underlies migraine with aura, activates trigeminal nociceptors, and causes periorbital mechanical allodynia. Spreading depolarization increases fos expression in the hypothalamic paraventricular nucleus (PVN). The PVN contains oxytocin and vasopressin neurons, which bind vasopressin receptors. We examined the effect of selective vasopressin 1A receptor antagonist relcovaptan and vasopressin 1B receptor antagonist nelivaptan on SD-induced migraine-relevant behavior. Single optogenetic SD (opto-SD) was induced in male and female Thy1-ChR2-YFP adult mice that received either (10 mg/kg, i.p.) relcovaptan, nelivaptan, or vehicle immediately after SD. One hour later, periorbital mechanical thresholds were tested with von Frey monofilaments. Spontaneous pain was tested with face grimace and photosensitivity with grimace to increasing light exposure. Open field was used to test anxiety-like behavior and locomotion at 4 hours. Opto-SD decreased periorbital thresholds, which recovered by 4 hours. Opto-SD also increased grimace and resulted in an upward shift in the grimace-light intensity curve. Opto-SD produced modest reductions in distance traveled related to increased immobility episodes. These impairments were accompanied by an SD-mediated increase in activation of PVN neurons, of which subpopulations stained positive for vasopressin or oxytocin. Relcovaptan prevented recovery from opto-SD-induced periorbital allodynia. Similarly, nelivaptan also prevented recovery from opto-SD-induced periorbital allodynia. However, there was no effect of either drug on opto-SD-induced grimace, photosensitivity, or locomotion. These data are consistent with an analgesic effect of endogenous vasopressinergic receptor activation in a mouse model of migraine.