Exploring Mechanisms of Action in Newer Pain Drugs for Migraine

A recent review explored the mechanism of a 5-hydroxytryptamine (5-HT 1f) agonist used in the treatment of acute migraine pain.

The first drug in this class, lasmiditan, was approved in the fall of 2019. It can cross the blood-brain barrier and act on receptors of the peripheral nervous system (PNS) and central nervous system (CNS). But how it works is not completely understood, said the authors of the review, published in The Journal of Headache and Pain.

Giving calcitonin gene-related peptide (CGRP) blockers can prevent migraines, a disabling condition that affects approximately 15% of Americans and affects more women than men.

The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons. Unlike 5-HT1B receptors—the target of pain-relieving triptans, which first entered the market in the 1990s—the activation of 5-HT1F receptors does not cause vasoconstriction. A small number of patients may not be able to take triptans due to cardiovascular reasons.

Nerve activity in the trigeminovascular pain pathway leads to the release of neuropeptides and neurotransmitters, such as CGRP and glutamate, and this activity is thought to overstimulate second-order neurons, which carry pain signals from the spinal cord to the thalamus, creating pain responses.

Lasmiditan activation of 5-HT1F receptors, found in the CNS, could potentially inhibit this release of CGRP and glutamate.

This could alleviate the main area of pain sensitization, while 5-HT1F receptors in the thalamus can block secondary central sensitization, which is linked with migraine progression and extracephalic cutaneous allodynia, the authors said.

In addition, evidence is accumulating that mitochondrial dysfunction might play a role in the development of migraine, and that 5-HT_1F receptors can promote mitochondrial biogenesis.

Reference

Clemow DB, Johnson KW, Hochstetler H, Ossipov MH, Hake AM, Blumenfeld AM. Lasmiditan mechanism of action — review of a selective 5-HT1F agonist.

J Headache Pain. Published online June 10, 2020. doi: 10.1186/s10194-020-01132-3