Objective: To determine whether intravenous infusion of substance P elicits headache and arterial dilation in healthy adults. Methods: In a double-blind, placebo-controlled, two-way crossover study, we randomly allocated healthy adults to receive either substance P (1.5 pmol/kg/min) or placebo (isotonic saline) by 20-minute intravenous infusion on separate experiment days. The primary endpoint was the incidence of headache within 12 hours after the infusion. Other endpoints included the area under the curve (AUC) for headache intensity scores over the 12-hour observation period and AUC changes in the superficial temporal artery (STA) diameter from baseline to 120 minutes post-infusion. Results: Twenty-one participants underwent randomization and completed both experiment days. Headache was reported by 15 (71%) of 21 participants following substance P, compared with two (10%) after placebo ( p  < 0.001). The AUC for headache intensity scores was significantly higher after substance P infusion than after placebo ( p  = 0.03). In addition, there was a significant STA diameter increase with substance P, compared with placebo ( p  = 0.005). Conclusions: Among healthy adults, substance P infusion elicited headache and arterial dilation. These findings support a role for substance P in headache pathogenesis and encourage further investigation in migraine and other headache disorders. Additional research is also needed to explore new therapeutic strategies targeting substance P or its downstream signaling. Trial Registration: CT identifier: NCT06632080.

Background: Persistent post-traumatic headache (PTH) is a prevalent and disabling neurological disorder, often attributed to mild traumatic brain injury and resembling migraine in clinical features. The underlying cortical morphometric changes and their relevance to persistent PTH remain unclear. Methods: This cross-sectional magnetic resonance imaging (MRI) investigation enrolled 103 adults with persistent PTH, 296 with migraine and 155 healthy controls (HC), to undergo structural MRI at 3T. Cortical surface area, thickness and volume were evaluated in FreeSurfer. The analyses applied cluster-determining thresholds of p < 0.001 and cluster-wise thresholds of p < 0.05, adjusted for age, sex and total intracranial volume. Results: Participants with persistent PTH exhibited larger surface area in the right anterior and posterior cingulate cortex ( p _cluster = 0.003), as well as the right superior parietal cortex/postcentral gyrus, compared to HC ( p _cluster < 0.035). No morphometric differences were observed between participants with persistent PTH and migraine (including subgroups: episodic, chronic, with aura without aura). Conclusions: These findings reveal morphometric alterations in persistent PTH, specifically within pain processing regions of the mid-cingulate and somatosensory cortex. Similar changes have been reported in migraine, suggesting a shared neurobiological substrate. These enlargements might reflect adaptations to recurrent nociceptive stimuli that sustain persistent PTH.