Activation of the trigeminal-autonomic reflex, involving the trigeminal ganglion, the superior salivatory nucleus and the sphenopalatine ganglion (SPG) is crucial in the pathophysiology of cluster headache (CH). Since pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) is present both in the SPG and the trigeminal ganglion (TG) and its role in migraine has been described, our aim was to determine the plasma PACAP-38 levels in different phases of episodic CH (ECH). Peripheral cubital fossa blood samples were taken during the ictal and inter-bout periods of male ECH patients and from age-matched healthy controls (n = 9). Plasma PACAP-38-like immunoreactivity (LI) was measured with specific and sensitive radioimmunoassay. Significantly lower plasma PACAP-38-LI was detected in the inter-bout period of ECH patients than in healthy controls. However, PACAP-38 was significantly elevated in the plasma during CH attacks as compared to the inter-bout phase in the same subjects (n = 5). This exploratory study suggests that PACAP-38 may be released during the attacks of ECH. Further patients and long-term follow-up are necessary to reveal its function.

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nonetheless, newly approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have a 50% responder rate ranging from 27 to 71.0%, whereas CGRP receptor inhibitors have a 50% responder rate ranging from 56 to 71%. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge of PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines.

Background: Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients.Methods: Female migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs,n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS).Results: Plasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling.Conclusions: Our results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.

Background: Recent data suggest that gene expression profiles of peripheral white blood cells can reflect changes in the brain. We aimed to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) and changes of plasma metabolite levels of migraineurs in a self-controlled manner during and between attacks.Methods: Twenty-four patients with migraine were recruited and blood samples were collected in a headache-free (interictal) period and during headache (ictal) to investigate disease- and headache-specific alterations. Control samples were collected from 13 age- and sex-matched healthy volunteers. RNA was isolated from PBMCs and single-end 75 bp RNA sequencing was performed using Illumina NextSeq 550 instrument followed by gene-level differential expression analysis. Functional analysis was carried out on information related to the role of genes, such as signaling pathways and biological processes. Plasma metabolomic measurement was performed with the Biocrates MxP Quant 500 Kit.Results: We identified 144 differentially-expressed genes in PBMCs between headache and headache-free samples and 163 between symptom-free patients and controls. Network analysis revealed that enriched pathways included inflammation, cytokine activity and mitochondrial dysfunction in both headache and headache-free samples compared to controls. Plasma lactate, succinate and methionine sulfoxide levels were higher in migraineurs while spermine, spermidine and aconitate were decreased during attacks.Conclusions: It is concluded that enhanced inflammatory and immune cell activity, and oxidative stress can play a role in migraine susceptibility and headache generation.

Migraine is a chronic neurological disorder that affects approximately 12% of the population. The cause of migraine headaches is not yet known, however, when the trigeminal system is activated, neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are released, which cause neurogenic inflammation and sensitization. Advances in the understanding of migraine pathophysiology have identified new potential pharmacological targets. In recent years, transient receptor potential (TRP) channels have been the focus of attention in the pathophysiology of various pain disorders, including primary headaches. Genetic and pharmacological data suggest the role of TRP channels in pain sensation and the activation and sensitization of dural afferents. In addition, TRP channels are widely expressed in the trigeminal system and brain regions which are associated with the pathophysiology of migraine and furthermore, co-localize several neuropeptides that are implicated in the development of migraine attacks. Moreover, there are several migraine trigger agents known to activate TRP channels. Based on these, TRP channels have an essential role in migraine pain and associated symptoms, such as hyperalgesia and allodynia. In this review, we discuss the role of the certain TRP channels in migraine pathophysiology and their therapeutic applicability.

Migraine is a complex neurovascular disorder, which causes intense socioeconomic problems worldwide. The pathophysiology of disease is enigmatic; accordingly, therapy is not sufficient. In recent years, migraine research focused on tryptophan, which is metabolized via two main pathways, the serotonin and kynurenine pathways, both of which produce neuroactive molecules that influence pain processing and stress response by disturbing neural and brain hypersensitivity and by interacting with molecules that control vascular and inflammatory actions. Serotonin has a role in trigeminal pain processing, and melatonin, which is another product of this pathway, also has a role in these processes. One of the end products of the kynurenine pathway is kynurenic acid (KYNA), which can decrease the overexpression of migraine-related neuropeptides in experimental conditions. However, the ability of KYNA to cross the blood–brain barrier is minimal, necessitating the development of synthetic analogs with potentially better pharmacokinetic properties to exploit its therapeutic potential. This review summarizes the main translational and clinical findings on tryptophan metabolism and certain neuropeptides, as well as therapeutic options that may be useful in the prevention and treatment of migraine.