Targeting TRP Channels For Novel Migraine Therapeutics

Abstract

Migraine is increasingly understood to be a disorder of the brain. In susceptible individuals, a variety of “triggers” may influence altered central excitability, resulting in the activation and sensitization of trigeminal nociceptive afferents surrounding blood vessels (i.e., the trigeminovascular system), leading to migraine pain. Transient receptor potential (TRP) channels are expressed in a subset of dural afferents, including those containing calcitonin gene related peptide (CGRP). Activation of TRP channels promotes excitation of nociceptive afferent fibers and potentially lead to pain. In addition to pain, allodynia to mechanical and cold stimuli can result from sensitization of both peripheral afferents and of central pain pathways. TRP channels respond to a variety of endogenous conditions including chemical mediators and low pH. These channels can be activated by exogenous stimuli including a wide range of chemical and environmental irritants, some of which have been demonstrated to trigger migraine in humans. Activation of TRP channels can elicit CGRP release, and blocking the effects of CGRP through receptor antagonism or antibody strategies has been demonstrated to be effective in the treatment of migraine. Identification of approaches that can prevent activation of TRP channels provides an additional novel strategy for discovery of migraine therapeutics.

Oxytocin Modulates Nociception as an Agonist of Pain-Sensing TRPV1

“…More evidence for this relationship was suggested by the effect of capsaicin on dilation of dural vessels (Akerman et al, 2003), and induction of trigeminal ganglion neuronal activity (Iwashita et al, 2013). However, the mechanisms by which TRPV1 contributes to initiating or propagating the neuronal signaling related to migraine are poorly understood (for review see (Dussor et al, 2014)). Our discovery of oxytocin as an endogenous agonist for the TRPV1 channel may shed more light onto the regulatory mechanisms that underlie physiology and pathology related to headaches and chronic migraine development.…”

“…This is consistent with the fact that therapeutic targeting of TRPV1 has been primarily advanced via exogenous agonists that lead to prompt channel desensitization. These treatment options are traditionally based on capsaicin-containing remedies, such as capsaicin cream or high concentration capsaicin patches (Dussor et al, 2014). Intranasal capsaicin administration has also been tested in treating migraine; similar to another TRPV1 agonist civanide, capsaicin reduced the frequency of cluster headache attacks (Diamond et al, 2000; Fusco et al, 2003).…”

Neurovascular contributions to migraine: Moving beyond vasodilation

“…Additionally, a situation could exist for example where activators of TRPA1 including environmental irritants (e.g. cigarette smoke, chlorine gas) which are well-known migraine triggers (for review see Dussor et al, 2014) are released into the blood and initiate signaling between meningeal nociceptors and endothelial cells. The full extent to which different ion channels expressed on endothelial cells contribute to processes culminating in nociceptor sensitization is currently unknown.…”

The Migraine Attack as a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory

“…Migraine triggers may be exposures that further increase oxidative stress . For certain putative triggers, hydrogen peroxide is a byproduct of detoxification, for example when tyramine is metabolized by monoamine oxidase or when alcohol is processed by cytochrome P450‐2E1.…”