TRPM8 and Migraine

Abstract

Migraine is among the most common diseases on earth and one of the most disabling, the latter due in large part to poor treatment efficacy. Development of new therapeutics is dependent on the identification of mechanisms contributing to migraine and discovery of targets for new drugs. Numerous genome-wide association studies (GWAS) have implicated the transient receptorpotential M8 (TRPM8) channel in migraine. This channel is predominantly expressed on peripheral sensory neurons and is known as the sensor for cold temperature in cutaneous tissue but is also expressed on deep visceral afferents where cold is not likely a stimulus. Consequently, a number of alternative endogenous agonists have been proposed. Apart from its role in cold sensation, TRPM8 also contributes to cold allodynia after nerve injury or inflammation, and it is necessary for cooling/menthol-based analgesia. How it might contribute to migraine is less clear. The purpose of this review is to discuss the anatomical and physiological mechanisms by which meningeal TRPM8 may play a role in migraine as well as the potential of TRPM8 as a therapeutic target. TRPM8 is expressed on sensory afferents innervating the meninges, and these neurons are subject to developmental changes that may influence their contribution to migraine. As in viscera, meningeal TRPM8 channels are unlikely to be activated by temperature fluctuations and their endogenous ligands remain unknown. Preclinical migraine studies show that activation of meningeal TRPM8 by exogenous agonists can both cause and alleviate headache behaviors, depending on whether other meningeal afferents concurrently receive noxious stimuli. This is reminiscent of the fact that cold can trigger migraine in humans but menthol can also alleviate headache. We propose that both TRPM8 agonists and antagonists may be potential therapeutics,

Quantitative Analysis of Mouse Dural Afferent Neurons Expressing TRPM8, VGLUT3, and NF200

“…Using FG to label dural afferent neurons in TRPM8 EGFPf/+ mice, we found that only 3%‐4% of dural afferent neurons express TRPM8 channels in adult mice, much lower than the percentage of total TG neurons expressing TRPM8 (10%). This is surprising, given that activation of dural TRPM8 channels significantly modifies headache‐related behaviors in rodent models . It is possible that we may underestimate the abundance of dural afferent neurons expressing TRPM8, as we removed the muscle and periosteal sheath on the skull before tracer application.…”

“…This is surprising, given that activation of dural TRPM8 channels significantly modifies headache-related behaviors in rodent models. [6][7][8] It is possible that we may underestimate the abundance of dural afferent neurons expressing TRPM8, as we removed the muscle and periosteal sheath on the skull before tracer application. This minimizes labeling of the pericranial afferent neurons in TG, but may damage the axon collaterals of dural afferent neurons that innervate pericranial tissues through the calvarial sutures 13,14 and cause neuronal death.…”

“…In a previous study, we have measured the abundance of dural afferent neurons that express neuropeptide calcitonin gene‐related peptide (CGRP), transient receptor potential (TRP) channel subfamily V member 1 (TRPV1) and subfamily A member 1 (TRPA1), respectively . However, using fluorescent retrograde tracer DiI (1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate), we were not able to label the cell body of dural afferent neurons expressing TRP channel melastatin 8 (TRPM8) in mouse trigeminal ganglion (TG), despite the fact that TRPM8‐expressing fibers are known to be present on mouse dura and dural TRPM8 channels have been shown to regulate headache‐related behaviors in rodent models . This presents a technical hurdle for further investigation of the neurochemical and physiological properties of TRPM8‐expressing dural afferent neurons.…”

“…4 However, using fluorescent retrograde tracer DiI (1,1 0 -dioctadecyl-3,3,3 0 ,3 0 -tetramethylindocarbocyanine perchlorate), we were not able to label the cell body of dural afferent neurons expressing TRP channel melastatin 8 (TRPM8) in mouse trigeminal ganglion (TG), despite the fact that TRPM8-expressing fibers are known to be present on mouse dura 5,6 and dural TRPM8 channels have been shown to regulate headache-related behaviors in rodent models. [6][7][8] This presents a technical hurdle for further investigation of the neurochemical and physiological properties of TRPM8-expressing dural afferent neurons. We speculated that sparse meningeal innervation and lack of extensive axonal branches might limit the likelihood and/or the amount of tracer taken up by individual TRPM8-expressing dural afferent neurons.…”

Migraine Care Challenges and Strategies in US Uninsured and Underinsured Adults: A Narrative Review, Part 2

“…Acutely, many patients find heat or cold packs, a hot shower, or a combination of these beneficial in dampening down the pain of migraine or tension‐type headache . Some patients find topical treatments such as herbal balms with small amounts of menthol or camphor (one of the main components of Tanacetum parthenium ) applied to the temples, forehead, or base of the neck helpful . Inhalation of lavender essential oil for 15 minutes may be helpful for some patients with migraine .…”