PACAP

In a double-blind, randomized crossover trial, intravenous infusion of PACAP38 (10 pmol/kg/min) versus vasoactive intestinal peptide (VIP) was administered to 12 patients with migraine without aura and 12 healthy controls. PACAP38 induced marked, prolonged dilation of the middle cerebral and superficial temporal arteries and provoked delayed migraine-like attacks in 7 of 12 migraine patients, whereas VIP did not induce delayed attacks. The results implicate the PACAP/receptor system in migraine pathophysiology and established PACAP38 as a human experimental trigger of migraine.

Researchers gave migraine patients a controlled infusion of the natural body peptide PACAP38 and compared it with a closely related peptide. PACAP38 widened blood vessels around the brain and triggered delayed migraine-like headaches in more than half of the patients, while the comparison peptide did not. This showed that PACAP is directly involved in causing migraine and pointed to it as a promising target for new migraine drugs.

In a heavily traumatized civilian cohort, blood levels of PACAP peptide correlated with PTSD diagnosis and symptom severity in females but not males. A single-nucleotide polymorphism (rs2267735) in an estrogen-response element of the PAC1 receptor gene (ADCYAP1R1) predicted PTSD diagnosis, symptoms, fear discrimination, and altered methylation, again in a sex-specific manner. ADCYAP1R1 mRNA was also induced by fear conditioning in rodent models and by estrogen in cell culture, supporting a PACAP/PAC1 pathway underlying abnormal fear responses in PTSD.

Scientists studying trauma survivors found that higher levels of the stress peptide PACAP in the blood tracked with more severe PTSD symptoms, especially in women. A specific genetic variant in the PACAP receptor gene, one influenced by the hormone estrogen, predicted who developed PTSD and how strongly they reacted to fear cues. The work suggests PACAP helps explain why some people, particularly women, are more vulnerable to PTSD and could guide future stress-disorder treatments.

Using high-resolution MR angiography in a double-blind crossover design, PACAP38 infusion induced migraine-like attacks accompanied by sustained dilation of extracranial arteries (middle meningeal and superficial temporal), while the middle cerebral artery showed no persistent dilation during attacks. Sumatriptan, a 5-HT1B/1D agonist, relieved the induced headache and selectively contracted the extracranial vessels. The findings localize PACAP38-triggered migraine to extracerebral rather than intracerebral arterial changes, refining the vascular component of migraine mechanisms.

Building on earlier work, researchers used detailed brain imaging to watch what happens when PACAP38 triggers a migraine. They found the headache was linked to widening of arteries outside the brain rather than inside it, and that the migraine drug sumatriptan both eased the pain and shrank those outer vessels. This clarified exactly which blood vessels are involved in PACAP-driven migraine and reinforced PACAP as a target for treatment.