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Metabotropic Glutamate Receptor 5: A Target for Migraine Therapy

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Metabotropic Glutamate Receptor 5: A Target for Migraine Therapy

Maggie W Waung et al. Ann Clin Transl Neurol.

Abstract

Introduction: Many 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.

Methods: We 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.

Results: The 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%.

Interpretation: Our 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.

Figures

Figure 1
Figure 1
Intravital microscopy experiments demonstrating effects of glutamatergic agents on neurogenic dural vasodilation. Following control responses to electrical stimulation, rats were injected intravenously with the mGlu5 inhibitor ADX10059 at 5 mg/kg (A, n = 6, clear circles), 20 mg/kg (A, n = 7, clear squares), sterile water (A and B, n = 7, filled circles), or MK‐801 4 mg/kg (B, n = 7, clear circles) and electrical stimulation repeated after 5, 10, 15, 30, 45, and 60 min. *P < 0.025, significance compared to control response.
Figure 2
Figure 2
Single unit extracellular recordings in anesthetized rats. (A) Original tracing from a dural‐evoked Aδ fiber neuronal response before and after ADX10059 (20 mg/kg). (B) Time course summary of stimulus evoked responses in the presence of vehicle control (sterile water or normal saline, n = 9) and ADX10059 (20 mg/kg, n = 9). (C) Sample poststimulus histogram (cumulative over 20 evoked responses) identifying Aδ fibers inhibited by ADX10059. (D) Time course summary of spontaneous cell firing in the presence of vehicle control or ADX10059. (E) Cell firing responses to light brush or noxious pinch over the V1 dermatome. Data are presented as mean ± SEM; *P < 0.0167 in (B) and *P < 0.008 in (D) when comparing to average of three baselines using Student's paired t test.
Figure 3
Figure 3
Immunohistofluorescent staining of group I mGlu receptors in naïve Sprague Dawley rats after intracardiac perfusion with 4% paraformaldehyde. (A, B) Light photomicrographs of medullary brain slices containing the TNC at 25× magnification. Immunostaining for (C) mGlu5 (green) and (D) mGlu1a (green) colabeled with NeuN (red) at 200× magnification. Immunostaining for (E) mGlu5 and (F) mGlu1a in the pyramidal layer of the cerebellum at 200× magnification. Scale bars = 200 μm (black), 50 μm (white).
Figure 4
Figure 4
Patient flow in the study.

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