Relcovaptan and Nelivaptan Prevent Recovery from Migraine-like Allodynia in Mice, Suggesting Endogenous Vasopressin Analgesia

Migraine with aura is a debilitating neurological disorder characterized by transient sensory disturbances preceding headache. The underlying mechanism involves cortical spreading depolarization (SD), a slow wave of neuronal and glial depolarization that activates trigeminal nociceptors, leading to periorbital mechanical allodynia. SD also increases fos expression in the hypothalamic paraventricular nucleus (PVN), a region rich in oxytocin and vasopressin neurons. Understanding the role of vasopressin 1 receptors (V1Rs) in modulating SD-induced pain is crucial, as current treatments often fall short in addressing the full spectrum of migraine symptoms, particularly allodynia.

Researchers investigated the role of vasopressin 1 receptors in a mouse model of migraine with aura. Single optogenetic SD (opto-SD) was induced in male and female Thy1-ChR2-YFP adult mice. Immediately after opto-SD, mice received either relcovaptan (10 mg/kg, i.p.), a selective vasopressin 1A receptor antagonist, nelivaptan (10 mg/kg, i.p.), a selective vasopressin 1B receptor antagonist, or vehicle. Periorbital mechanical thresholds were assessed 1 hour post-SD using von Frey monofilaments. Spontaneous pain was measured via face grimace scores, and photosensitivity by grimace response to increasing light. Anxiety-like behavior and locomotion were evaluated using an open field test at 4 hours post-SD.

Opto-SD induction significantly decreased periorbital mechanical thresholds, indicating allodynia, which spontaneously recovered by 4 hours in vehicle-treated mice. Opto-SD also increased face grimace scores and caused an upward shift in the grimace-light intensity curve, signifying photosensitivity. These behavioral impairments were accompanied by an SD-mediated increase in activation of PVN neurons, with subpopulations staining positive for vasopressin or oxytocin. However, the administration of V1R antagonists profoundly altered the pain recovery profile:

Relcovaptan prevented the natural recovery from opto-SD-induced periorbital allodynia, maintaining reduced thresholds. Similarly, nelivaptan also prevented the recovery from opto-SD-induced periorbital allodynia, suggesting a critical role for both V1A and V1B receptors in endogenous pain modulation. Neither relcovaptan nor nelivaptan had any significant effect on opto-SD-induced grimace, photosensitivity, or locomotion, indicating a specific role in mechanical allodynia rather than other pain or anxiety-like behaviors.