Glutamate as a Therapeutic Substrate in Migraine

Abstract

Recurrent and intense headache is a well appreciated cardinal feature of migraine, a common and incapacitating neurological disorder. Often, there are associated canonical sensory abnormalities, such as light and sound sensitivity, as well as associated nausea. Given this phenotype of disordered sensory processing and, in a third of patients, the phenomenon called aura accompanying migraine attacks, it has been suggested that the pathophysiology of migraine is likely to involve glutamate, the main excitatory neurotransmitter in the central nervous system (CNS). Glutamate plays a role in nociception, central sensitization, and cortical spreading depression (CSD), three processes that are deemed important in migraine biology. With an emphasis on the therapeutic potential of targeting various glutamate receptors in migraine, this review will discuss the currently available literature and emerging findings on the role of targeting glutamatergic pathways for the treatment of migraine. A thorough literature review was carried out on the functions of both metabotropic glutamate receptors (mGluRs), and the ionotropic glutamate receptors (NMDA, AMPA, and kainate) in migraine pathogenesis. The ever-present need for new treatments, the role of glutamate in the migraine aura phenomenon, and the consequences of monogenic migraine mutations on mediating prolonged, complex, or permanent aura are all discussed, culminating in a suggestion that glutamatergic targeting may hold particular promise in the management of migraine aura. There are plausible roles for metabotropic receptors in regulating pain processing in important migraine-related brain structures, like the thalamus and trigeminal nucleus. Similarly, ionotropic receptors contribute to excitatory neurotransmission and neuronal hyperexcitability. Recent studies have shown preclinical and early clinical results for treatments targeting these receptors, but there are still significant issues with treatment response, including drug transport, side effects, and efficacy. With ongoing and emerging discoveries in the field, there is increasing promise of new migraine medications targeting glutamate receptors. For bench to bedside translation in this area, continued study of the molecular basis of migraine, receptor subtypes, and exploration of potential drug delivery methods are needed.

Keywords: AMPA; NMDA; excitotoxicity; genetics; glutamate; iGluR; kainate; mGluR; migraine.

Figure 1

Ionotropic glutamate receptors (iGluRs). The axon (yellow) releases glutamate (Glu) upon excitation, promoting ionic flux depending on the receptor activated. AMPA and kainate receptor activation leads to inward flux of sodium (Na⁺) into the postsynaptic cell, and efflux of potassium (K⁺), whilst NMDA receptor activation leads to displacement of magnesium (Mg²⁺) and sodium and calcium (Ca²⁺) entry into the cell. Figure made using Biorender.com.

Figure 2

Metabotropic glutamate receptors (mGluRs). Metabotropic receptors are classified into groups depending on their pharmacology and function based on downstream cellular pathways. Group 1 receptors have been most commonly researched in migraine, and stimulate phospholipase C (PLC) and the hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP2), producing inositol (1,4,5)-triphosphate (IP3) and diacylglycerol (DAG). IP3 diffusion onto the endoplasmic reticulum promotes Ca²⁺ release to the cytoplasm. Group II and III mGluRs inhibit adenylate cyclase (AC), therefore affecting downstream mechanisms via cyclic adenosine monophosphate (cAMP) and phosphokinase A (PKA). Figure made using Biorender.com.