Function and postnatal changes of dural afferent fibers expressing TRPM8 channels
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RESEARCH
Function and postnatal changes of dural afferent fibers expressing TRPM8 channels Lynn Ren1, Ajay Dhaka2 and Yu‑Qing Cao1*
Abstract Background: Genome-wide association studies have identified TRPM8 (transient receptor potential melastatin 8) as one of the susceptibility genes for common migraine. Here, we investigated the postnatal changes of TRPM8-express‑ ing dural afferent fibers as well as the function of dural TRPM8 channels in mice. Results: First, we quantified the density and the number of axonal branches of TRPM8-expressing fibers in the dura of mice expressing farnesylated enhanced green fluorescent protein (EGFPf ) from one TRPM8 allele between postna‑ tal day 2 (P2) to adulthood. The number of axonal branches on individual dural EGFP-positive fibers was decreased by 30% between P2 and P11. The density of dural EGFP-positive fibers was subsequently reduced by 50% between P16 and P21. Conversely, the density and the number of branches of axons expressing calcitonin gene-related peptide remained stable in postnatal mouse dura. The density of TRPM8-expressing fibers innervating the mouse cornea epithelium was significantly increased from P2 to adulthood. Next, we tested the function of dural TRPM8 channels in adult mice and found that TRPM8 agonist menthol effectively inhibited the nocifensive behavior evoked by dural application of inflammatory mediators. Conclusions: Our results indicate that the TRPM8-expressing dural afferent fibers undergo cell- and target tissuespecific axonal pruning during postnatal development. Activation of dural TRPM8 channels decreases meningeal irritation-evoked nocifensive behavior in adult mice. This provides a framework to further explore the role of postnatal changes of TRPM8-expressing dural afferents in the pathophysiology of pediatric and adult migraine. Keywords: Migraine, Headache, TRPM8, CGRP, Dural afferent fibers Background Migraine is a common neurovascular disorder that affects more than 10% of the general population [1]. It is characterized by recurrent attacks of debilitating headaches and other neurological symptoms [2]. It is well established that the activation and sensitization of the primary afferent neurons (PANs) innervating the dura and cerebral blood vessels underlie the pathogenesis of headache [3–5]. Migraine has a strong genetic component. Recent genome-wide association studies of common migraine have discovered several susceptibility genes, including the gene encoding the transient receptor potential melastatin 8 (TRPM8) channel [6–8]. The TRPM8 single *Correspondence: [email protected] 1 Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA Full list of author information is available at the end of the article
nucleotide polymorphism variant is 950 bp upstream of the transcription start site for TRPM8 mRNA [6], and has been verified in several migraine cohorts [6–8]. Whether and how it affects the expression of TRPM8 channels as well as
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