Novel Therapeutic Targets for Migraine: Recent Findings

In this video, Amynah Pradhan, PhD, Associate Professor, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, discusses her State of Science presentation given at Neurology Week. Dr. Pradhan describes recent findings from her lab, including novel therapies for migraine and headache disorders.

Read the Transcript:

Amynah Pradhan, PhD:  My name is Amynah Pradhan. I'm an associate professor in the Department of Psychiatry at the University of Illinois at Chicago. I wanted to give you a little bit of a summary about the presentation on the State of Science that I've made for Neurology Week.

I have summarized a couple of projects that have recently been published from my lab in this last year. My lab is very interested in finding novel therapies for migraine and headache disorders in general.

As we know, a large number of people suffer from migraine, and although there are a lot of novel therapies that have recently been approved, patients still have headaches that are not well-treated by a number of different medications. A driving force in my lab has been to try to find novel therapeutic targets for migraine.

The first story that I want to tell is about the role of the delta opioid receptor in migraine. A lot of us are very familiar with the opioid receptors, and when we think about opioid receptors, we think of the mu-opioid receptor. The reason being is that currently available opioid treatments primarily act through the mu-opioid receptor.

As we know, this has a number of significant adverse consequences, including high abuse liability and the propensity to cause medication overuse headache.

If we look within that same receptor family, we can find the delta opioid receptor, which has pain-relieving properties but does not have abuse liability and also has antidepressant and anxiolytic effects.

Our lab has done a lot of work over the last five to eight years, looking at the role of the delta opioid receptor in various headache disorders, including acute and chronic migraine. What we find is that in preclinical models, delta activation or agonists are very effective.

In fact, this has led to at least one pharmaceutical company developing their delta agonists for the treatment of migraine, and that's currently in phase II clinical trials. The most recent work from our lab had to do with, how is it that delta agonists may be relieving migraine-associated pain?

What we did was to look at the expression of the delta opioid receptor with components of the CGRP family. We examined co-expression between the delta opioid receptor and CGRP as well as between the delta opioid receptor and the CGRP receptor components.

What we found was that within the trigeminal system, in the trigeminal ganglia, there seems to be a fairly balanced co-expression between the delta opioid receptor and the CGRP receptor as well as between the delta opioid receptor and CGRP separately.

Whereas, in the trigeminal nucleus caudalis, we found that there was an extremely high co-expression between the delta opioid receptor and the CGRP receptor. The reason that this is important to think about is because this sheds some light on the mechanism through which delta agonists may relieve migraine-associated pain.

Because the delta opioid receptor is a Gi G-protein-coupled receptor, and so therefore, when this receptor is activated, it results in inhibition of the cell. The CGRP receptor's a Gs G-protein-coupled receptor, so therefore, when CGRP binds to its receptor, the postsynaptic cell then gets activated.

What this means is that in cells where the delta opioid receptor is co-expressed with CGRP, that results in decreased CGRP release, which would then result in decreased pain signaling.

When the delta opioid receptor is co-expressed with the CGRP receptor, which seems to be more the case when we're talking about central regions, in that case, activation of the delta opioid receptor would prevent the signaling of the CGRP receptor.

Even though there may be a lot of CGRP present, the signal can't get pushed forward, because the delta opioid receptor is inhibiting the same cell that the CGRP receptor is on.

It goes to show that there might be two distinct ways in which activation of the delta opioid receptor can then result in decreased CGRP receptor signaling response. That paper was recently published in Pain.

The second story that I would like to tell you about is a little bit different, looking at the mechanism of migraine chronification. In this case, we looked at the cytoarchitecture of neurons in the brain as well as neuronal complexity.

The reason why we got this idea was because in a lot of other chronic conditions, especially in a lot of neuropsychiatric conditions as well as in some chronic pain states, there's some evidence to show that there's altered neuronal complexity when the condition becomes chronic.

What we did was we wanted to explore whether in a chronic migraine state, there may also be altered neuronal complexity. We used two different preclinical models of migraine, one in which we used a known human migraine trigger, nitroglycerin, in mice.

This causes, with repeated treatment, can cause severe and chronic allodynia. The other model that we used was cortical spreading depression, which is a model of migraine aura. It's thought to be a physiological correlate of migraine aura.

What we found was that in both of these models, if we looked in specific brain regions involved with either pain processing or involved with cortical activity, we found that there was a significant decrease in neuronal complexity.

The way that we look at that is we do a Golgi stain, and then we can then trace the neuron and look to see what are the changes in the number of neurites and how complex those neurites are.

In fact, this might sound shocking, but the bottom line is that cells are constantly in a state of flux. Cells are constantly growing and retracting, in response to its environment.

What we're seeing is that within these models of chronic migraine, we, in fact, are seeing that there's blunted neuronal complexity in this particular state. Upon thinking about that, we're like, "OK, well, how could we then get at this and try to restore the neuronal complexity?"

This is where we started to explore the actual dynamics of the cytoskeleton. Each cell, the way that the cell maintains its shape is through something called its cytoskeleton, which is made up of microtubules. Microtubules are very dynamic.

As I mentioned, the cells are constantly growing, they're retracting, they're sending out processes, making dendritic spines. This whole process is regulated very carefully through these microtubule dynamics, which are based on chemical modifications on the tubulin itself, which then tells the microtubules, "OK, you need to grow here, you need to retract there."

In fact, there's a lot of evidence that shows that when microtubules are acetylated -- they have a lot of acetyl groups on them -- they tend to be more flexible and more stable. If you take those acetyl groups off, then the microtubules are more brittle and prone to breakage.

What we thought is that, "OK, if we could stabilize the microtubules, if we could increase acetylation, would we then be able to restore neuronal complexity and also then see these pain relief or decreased cortical spreading depression events?"

What we found is that if we use something called an HDAC6 inhibitor, which then results in increased acetylated tubulin, so increased stable microtubules, not only did we restore the neuronal complexity that we had lost in these preclinical models of migraine.

We also found that these HDAC6 inhibitors were pain-relieving within these models and also decreased the number of cortical spreading depression events associated with migraine aura.

This is very interesting. On one hand, first of all, it opens up a whole new class of novel therapeutic targets associated with cytoskeletal flexibility, things like HDAC6.

It also tells us something about how maybe this is why people end up with chronic migraine, or how the transition happens from episodic to chronic migraine, where all of the sudden, maybe their neurons are not as flexible or as responsive as they once were.

This is how they've ended up in these situations where maybe there's maladaptive synapses, where the cell cannot shut things down, where it might have been able to shut things down or it can't grow into synapses that it should be growing into. This might be what is causing or maintaining this chronic migraine state.

What was interesting is that we then used a known migraine therapeutic, so we used a CGRP receptor antagonist. What we found is that with the treatment of the CGRP receptor antagonist, we also found that this restored neuronal complexity, and correspondingly also, resulted in decreased allodynia.

This is very important, because CGRP receptor antagonists are not known to specifically target microtubules. There's probably some indirect mechanism through which it's resulting in this restored neuronal complexity.

It shows that there's a correspondence, that there's blunted neuronal complexity in this chronic migraine state and that restoration of this blunted neuronal complexity can be a hallmark of an effective migraine therapeutic.

Thank you very much for joining me in this session. I hope you enjoy some of our work.