Papers of the Week

Migraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before the emergence of pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress is a common migraine trigger that engages hypothalamic dynorphin/kappa opioid receptor (KOR) signaling and increases circulating prolactin. Prolactin acts at both long and short prolactin receptor isoforms (PRLR-L and PRLR-S) that are expressed in trigeminal afferents. Following down-regulation of PRLR-L, prolactin signaling at PRLR-S sensitizes nociceptors selectively in females. We hypothesized that stress may activate KOR on tuberoinfundibular dopaminergic neurons to increase circulating prolactin leading to female-selective sensitization of trigeminal nociceptors through dysregulation of PRLR isoforms. A mouse two-hit hyperalgesic priming model of migraine was used. Repeated restraint stress promoted vulnerability (i.e., first-hit priming) to a subsequent subthreshold (i.e., second-hit) stimulus from inhalational umbellulone, a TRPA1 agonist. Periorbital cutaneous allodynia served as a surrogate of migraine-like pain. Female and male KORCre; R26lsl-Sun1-GFP mice showed high percentage of KORCre labeled neurons co-localized in tyrosine hydroxylase positive cells in the hypothalamic arcuate nucleus (ARC). Restraint stress increased circulating prolactin to a greater degree in females. Stress-primed, but not control, mice of both sexes developed periorbital allodynia following inhalational umbellulone. Gi-DREADD activation (i.e., inhibition through Gi-coupled signaling) in KORCre neurons in the ARC also increased circulating prolactin and repeated chemogenetic manipulation of these neurons primed mice of both sexes to umbellulone. CRISPR/Cas9 deletion of ARC KOR prevented restraint stress-induced prolactin release in female mice and priming from repeated stress episodes in both sexes. Inhibition of circulating prolactin with systemic cabergoline, a dopamine D2 receptor agonist, blocked priming selectively in females. Repeated restraint stress down-regulated PRLR-L in the trigeminal ganglia of female mice. Deletion of PRLR in trigeminal ganglia by nasal CRISPR/Cas9 targeting both PRLR isoforms prevented stress-induced priming in female mice. Stress-induced activation of hypothalamic KOR increases circulating prolactin resulting in trigeminal downregulation of PRLR-L and pain responses to a normally innocuous TRPA1 stimulus. These are the first data that provide a mechanistic link between stress-induced hypothalamic activation and the trigeminal nociceptor effectors that produce trigeminal sensitization and migraine-like pain. This sexually dimorphic mechanism may help to explain female prevalence of migraine. KOR antagonists, currently in phase II clinical trials, may be useful as migraine preventives in both sexes, while dopamine agonists and prolactin/PRLR antibodies may improve therapy for migraine, and other stress-related neurological disorders, in women.