PACAP38 induces migraine-like attacks in patients with migraine without aura

Abstract

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0-2 h) and post-hospital (2-12 h) phases. Mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2-11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in V(MCA) and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.

The PACAP Receptor: A Novel Target for Migraine Treatment

“…Nonetheless, the ability of PACAP-38 to induce migraine, in contrast to VIP, strongly points to PAC 1 receptor activation as a possible mediator of migraine. Experimental data noted in this review suggest that vasodilatation, 10,33,35,36 mast cell degranulation, 44,62 and neurogenic inflammation 62 are induced by the VPAC receptors and therefore do not seem important in PACAP-38-induced migraine. Instead, PACAP-38 might modulate the PAC 1 receptors at the second-order trigeminal neurons.…”

“…Recent studies point to the involvement of PACAP in migraine pain. 10 Here we review the evidence on how PACAP might be implicated in specific receptor activation during migraine attacks and discuss how the PAC 1 receptor could be a novel target for migraine treatment.…”

Role of pituitary adenylate cyclase-activating polypeptide (pacap) in the trigeminovascular system: preclinical and clinical results

“…A clinical study has revealed that intravenously administered PACAP-38 induces headache in healthy volunteers and migraine-like attacks in patients with migraine without aura (6 h on average after the start of the infusion) [27], similarly to the effect of NTG in causing headache [74,75]. Moreover, the decrease of the mean blood flow velocity in the middle cerebral artery and the increase of the diameter of the superficial temporal artery were also observed in the PACAP study of the migraineurs.…”

“…Among the numerous "migraine-related" processes and substances, recent studies have potentially implicated the vasoactive PACAP in the pathophysiology, and hence in the future therapy of migraine [27,28].…”

“…Numerous animal experiments [59,60,62,65] and some clinical studies [27,28] have pointed out the key role of PACAP in nociceptive signalling mechanisms. Although its involvement in migraine has recently been indicated by human data [27,223], and its immunohistochemical localization has been described in the TS [35], our work provides the first experimental evidence that its concentration is specifically altered in the TNC and the plasma in response to stimulation of the TS in rat models.…”