Metabotropic glutamate receptor 5: a target for migraine therapy

Abstract

IntroductionMany patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine‐specific target, the mGlu5 receptor.MethodsWe studied the effect of mGlu5 blockade using ADX10059, on neuronal firing in the trigeminocervical complex (TCC) and durovascular effects of nociceptive trigeminovascular activation in the anesthetized rat. The clinical potential of the mGlu5 mechanism was tested with ADX10059 orally in a double‐blind placebo‐controlled, parallel group, clinical trial.ResultsThe negative allosteric mGlu5 modulator ADX10059 attenuated dural vasodilator responses to meningeal stimulation in a dose‐dependent manner, comparable to naratriptan, while the N‐methyl‐d‐aspartate receptor blocker MK‐801 had no effect. ADX10059 reduced responses of trigeminocervical neurons to dural stimulation, most strikingly affecting their spontaneous firing rate. Immunostaining identified mGlu5 and not mGlu1a receptors in the TCC. The primary efficacy endpoint for the clinical trial, 2 h pain free, demonstrated a significant effect of ADX10059 375 mg, 17%, versus placebo, 5%. No serious adverse events were reported at the primary dose, with transient dizziness being the most common treatment‐emergent event at 48%.InterpretationOur findings provide preclinical and clinical proof of concept establishing mGlu5 as a novel therapeutic target in the treatment of migraine. Although ADX10059 is unsuitable as a therapeutic candidate, because of hepatoxicity detected in a subsequent study, the data open a new direction for migraine research and therapy.

Glutamate and Its Receptors as Therapeutic Targets for Migraine

“…In relationship to migraine and trigeminal pain, mGluRs belonging to group I, in particular mGluR5, are the most investigated. The mGluR5 are located in trigeminal sensory afferents [93,94], the trigeminal ganglion [95], and in the TCC [96][97][98][99]. From a functional perspective, the receptor has been shown to be involved in several types of pain including inflammatory and neuropathic pain [100,101].…”

“…It may also interact with other receptor systems involved in the modulation of pain signals including opioid [47,103] and TRPV1 [100,101] channels and in this way even play a significant role in the chronification of pain. In the context of migraine, targeting these receptors in an in vivo rodent model with the negative allosteric modulator ADX10059 has revealed that the compound attenuates neurogenic dural vasodilation induced by electrical stimulation of the middle meningeal artery as well as stimulus-evoked and spontaneous central nociceptive transmission through the TCC [96] indicating an action at peripheral and central receptors. As these results suggested a therapeutic potential in migraine, a randomized controlled trial has been conducted which demonstrated clinical efficacy [96].…”

Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

“…These metabolites are present in the nano/micromolar range in the human brain and they act partly on the glutamatergic system [ 13 , 14 ]. Both ionotropic and metabotropic glutamate receptors are involved in mechanisms related to migraine [ 15 , 16 ], but N-methyl-D-aspartate (NMDA) receptors have a pronounced role in the onset of cortical spreading depression (CSD) [ 17 , 18 ], the development of hyperalgesia [ 19 ] and the activation of migraine generators [ 20 , 21 ]. Since the inhibition of NMDA receptors is believed to protect against glutamate-caused excitotoxicity and KYNA has a competitive antagonist effect on these receptors [ 4 ], it is possible that the KP has therapeutic potential in headache disorders.…”

Kynurenine Pathway of Tryptophan Metabolism in Migraine and Functional Gastrointestinal Disorders

“…l -Trp metabolites may act on the glutamatergic system, which is involved in pain transmission, central sensitization, and CSD (reviewed in [ 104 ]). The glutamatergic ionotropic and metabotropic receptors are involved in migraine pathogenesis [ 78 , 105 , 106 ]. A subset of these receptors, NMDA receptors, is important in the onset of CSD and activation of the migraine generator, a brainstem area that is specifically activated during migraine attack [ 107 , 108 ].…”