Suvorexant prevents male-specific post-traumatic headache by blocking orexin B/OX2R signaling in mTBI mice
Background
Mild traumatic brain injury (mTBI) frequently leads to post-traumatic headache (PTH), which can be transient (APTH) or persistent (PPTH) and often resembles migraine. Current treatments for PTH are often inadequate, highlighting a critical need for targeted therapies. Previous research indicates that orexin B sensitizes dorsal root ganglion neurons in male but not female subjects across species, and supradural orexin B/orexin receptor 2 (OX2R) signaling can induce migraine-like pain specifically in male mice. This sex-specific involvement of the orexin system suggests a potential therapeutic target for PTH, particularly given its known role in pain modulation and arousal.
Study Design
Researchers induced mTBI in male and female mice, observing transient cephalic allodynia as a surrogate for APTH. After APTH resolution, PPTH was reinstated using innocuous stress or a subthreshold dose of umbellulone, a TRPA1 agonist. To investigate the role of orexin signaling, subthreshold supradural orexin B was administered. Trigeminal OX2R expression was edited via intranasal CRISPR/Cas9 plasmid delivery. Daily oral suvorexant, a dual orexin receptor antagonist (DORA), was administered immediately after mTBI or after APTH resolution. EEG/EMG was used to assess sleep architecture, and immobility defined sleep, to rule out sleep modulation as the primary mechanism of suvorexant's effects.
Results
mTBI induced transient cephalic allodynia in both sexes, but subthreshold supradural orexin B induced PPTH only in male mTBI mice. Intranasal CRISPR/Cas9 plasmid delivery, which edited trigeminal OX2R expression, prevented both APTH and the development of PPTH selectively in male mTBI mice. Daily oral suvorexant, administered immediately after mTBI, prevented both APTH and the transition to PPTH. This suggests a critical role for OX2R signaling in male PTH. Importantly, the study found: > Critically, starting suvorexant treatment after resolution of APTH also prevented stress- or umbellulone-induced PPTH. This indicates efficacy even in established PPTH. EEG/EMG-defined sleep architecture and immobility-defined sleep were not disrupted in this mTBI model, suggesting that suvorexant's benefits are unlikely related to sleep modulation, but rather to direct pain pathway modulation.
Key Findings
- mTBI-induced persistent post-traumatic headache (PPTH) was selectively induced by orexin B in male mice.
- CRISPR/Cas9 editing of trigeminal
OX2Rprevented APTH and PPTH development only in male mTBI mice. - Daily oral suvorexant prevented both APTH and PPTH when initiated immediately after mTBI.
- Starting suvorexant after APTH resolution also prevented stress- or umbellulone-induced PPTH.
- Suvorexant's benefits were independent of sleep modulation in this mTBI model.
Why It Matters
This research reveals a male-specific mechanism for post-traumatic headache (PTH) maintained by orexin B/OX2R signaling, offering a novel therapeutic avenue. The finding that suvorexant, an FDA-approved dual orexin receptor antagonist (DORA), can prevent both acute PTH and its transition to persistent forms, and even treat established persistent PTH, is highly significant. This suggests that existing DORAs could be repurposed to treat PTH in men, potentially offering a new, effective protocol where current options are limited. The ability to intervene even after APTH resolution means clinicians could have a window to prevent chronic pain, impacting patient quality of life. Further human trials are needed, but this preclinical data provides a strong rationale for investigating suvorexant in male PTH patients.
suvorexant
post-traumatic-headache
mtbi
orexin
ox2r
pain