An outlook on the trigeminovascular mechanisms of action and side effects concerns of some potential neuropeptidergic antimigraine therapies

ABSTRACT

Introduction: In addition to serotonin (5-hydroxytryptamine; 5-HT) and other (neuro)mediators, the role of neuropeptides in migraine pathophysiology is relevant. Indeed, while some molecules interfering with calcitonin gene-related peptide (CGRP) transmission have recently been approved for clinical antimigraine use, other neuropeptides with translational use are in the pipeline. Among others, hypothalamic neuropeptides such as pituitary adenylate cyclase-activating peptide (PACAP), oxytocin (OT), and orexins stand out as potential novel targets to treat this neurovascular disorder.

Areas covered: Based on the aforementioned findings, the present review: (i) summarizes the current knowledge on the role of the above neuropeptides in the trigeminovascular system, and migraine pathophysiology; and (ii) discusses some issues related with the mechanisms of action and side effects concerns that could be elicited when targeting the CGRPergic, PACAPergic, oxytocinergic and orexinergic systems.

Expert opinion: Specific antimigraine pharmacotherapies have evolved from the enhancement of serotonergic 5-HT_1B/1D/1F transmission to the use of compounds interacting with neuropeptidergic systems. Canonically, neuropeptides cause an array of complex intracellular mechanisms that, after modifying neuronal and/or vascular transmission, result in antimigraine action and also potential side effects. Furthermore, due to the chemical nature of some molecules targeting the above neuropeptidergic transmission (e.g., monoclonal antibodies, peptides), there are some limiting pharmacokinetics issues.

KEYWORDS:

• Adverse side effects
• cgrp
• migraine
• headache
• orexins
• oxytocin
• pacap
• pain

Article highlights

• Understanding the role of the trigeminovascular system in the pathophysiology of migraine has been relevant in the development of novel antimigraine pharmacotherapies.

• Currently, migraine is considered a neurovascular disorder associated with: (i) low plasma concentrations of serotonin (5-hydroxytryptamine; 5-HT) and/or high plasma concentrations of calcitonin gene-related peptide (CGRP); (ii) vasodilatation of intracranial and extracranial arteries, which are a significant source of pain in migraine, seemingly associated with CGRP release from trigeminal sensory nerves; and (iii) activation of the trigeminovascular system at the peripheral and central levels.

• Consequently, and regardless of their site of action, the development of molecules interfering with CGRPergic transmission (gepants and monoclonal antibodies [mAbs]) offers a considerable improvement to prevent migraine attacks.

• Despite this progress, not all patients respond to current pharmaco-therapies; while the development of molecules with minor adverse events is necessary. This implies that, in some patients, several other molecules may also be involved. Within this context, various hypothalamic neuropeptides such as pituitary adenylate cyclase-activating peptide (PACAP), oxytocin (OT) and orexins also seem to play a role in migraine pathophysiology.

• These hypothalamic neuropeptides exert important effects in the trigeminovascular system by facilitating or disrupting the nociceptive trigeminal transmission.

• mAbs against PACAP are currently under randomized clinical trials.

• More recently, OT has emerged as an analgesic neuropeptide, and some small clinical assays suggest that intranasal delivery of this molecule results in antimigraine effects.

• Disrupted orexinergic systems can contribute to migraine nociception; as such, this system represents a potential therapeutic target for antimigraine action.

• This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors acknowledge the financial support granted by Consejo Nacional de Ciencia y Tecnología (CONACyT Mexico) to (i) A González-Hernánde (Fondo Sectorial de Investigación para la Educación, Grant No. A1-S-23631); and (ii) CM Villalón (Grant No. 219707). Furthermore, CM Villalón acknowledges the SEP-Cinvestav Research Support Fund (Grant No. 50).”