Neuronal complexity is attenuated in preclinical models of migraine and restored by HDAC6 inhibition

Abstract

Migraine is the third most prevalent disease worldwide but the mechanisms that underlie migraine chronicity are poorly understood. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on dynamic microtubules. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated mouse models of migraine to show that HDAC6-inhibition is a promising migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in headache-processing regions, which were reversed by HDAC6 inhibition. Cortical spreading depression (CSD), a physiological correlate of migraine aura, also decreased cortical neurite growth, while HDAC6-inhibitor restored neuronal complexity and decreased CSD. Importantly, a calcitonin gene-related peptide receptor antagonist also restored blunted neuronal complexity induced by nitroglycerin. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and effective migraine therapies might include agents that restore microtubule/neuronal plasticity.

Deep Learning-Based Grimace Scoring Is Comparable to Human Scoring in a Mouse Migraine Model

“…In a previous work, we utilized the MGS in a mouse migraine model induced by repeated intermittent NTG injections [ 22 ]. In this model, both paw allodynia [ 27 ] and orbital allodynia [ 28 , 29 , 30 ] were found due to TGVS activation. This model can be employed as a platform for developing abortive and preventive treatments for migraine since mechanical allodynic responses induced by acute and chronic NTG treatments are sensitive to sumatriptan and topiramate, the abortive and preventive medicines of migraine, respectively [ 31 ].…”

Migraine and peripheral pain models show differential alterations in neuronal complexity

“…For CRPS we intended four mice/group with eight neurons traced/mouse/region. These numbers were based on our previous study 33 . Because we investigated changes at the cellular level, an individual neuron represented a single sample.…”

“…These numbers were based on our previous study. 33 Because we investigated changes at the cellular level, an individual neuron represented a single sample.…”

Delta opioid receptors in Nav1.8 expressing peripheral neurons partially regulate the effect of delta agonist in models of migraine and opioid-induced hyperalgesia

“…The procedure we used in this study was based on previous work ( Dripps et al, 2020 , Bertels et al, 2021 , Bertels et al, 2021 ). Mice were anesthetized with isoflurane (induction 3–4 %; maintenance 0.75 to 1.25 %; in 67 % N 2 / 33 % O 2 ) and placed in a stereotaxic frame on a homeothermic heating pad.…”