Dr Frank Porreca Discusses New Developments in Migraine Science

One development in migraine science is the hypothesis that sex differences in migraine prevalence may be accounted for, in part, at the nociceptor level, said Frank Porreca, PhD, professor of pharmacology and anesthesiology at the University of Arizona and a member of the Department of Collaborative Research at Mayo Clinic in Arizona.

Transcript:

The American Journal of Managed Care® (AJMC®): Can you give a brief overview of your work?

Dr. Porreca: My work is focused on mechanisms of pain, and also mechanisms that are relevant to migraine and to post traumatic headache. We use preclinical models in order to understand mechanisms, in order to understand circuits that might be promoting pain responses. Our focus is on trying to understand these mechanisms so that we can help to explain some of the symptoms that are observed in humans. And then to use that understanding to help to advance the development of novel therapies that can be taken back to humans. It's sort of a reverse translation, clinical observation to the laboratory and then use of the laboratory investigation to try to advance novel therapies to humans. I guess I would refer to my work as clinically informed basic science.

AJMC®: What were some of the year's most important findings when it comes to migraine science for clinicians? Were there any that surprised you?

Dr. Porreca: There are a couple of themes that I think are important that have emerged in the past year. I guess we would all possibly agree that 2020 has not been the very best year from many different points of view. But in terms of the science and the science around migraine and post traumatic headache, I think that we have had some significant advances. One of the most important things that has started to emerge is this concept of sexually dimorphic mechanisms that may be driving pain. Of course, migraine is a very complex neurological disorder in humans with multiple symptoms and multiple circuits in the brain that may be underlying those clinical symptoms. So the preclinical point of view, we really can't study migraine as a disease entity in and of itself. So what we do is we take some of these symptoms and we try to understand the mechanisms that might be promoting those symptoms.

One of the most bothersome symptoms of migraine in patients is the pain phase. There are multiple phases of migraine, the premonitory phase, an aura pain phase, postdrome phase. Preclinical laboratories generally focus on the pain phase, although there's emerging data on increased sensitivity to light and to sound and other features of migraine. The way that we try to understand that is to understand that the pain may result from the activation of nociceptors, those sensory fibers that mediate the pain response, that innervate, the cranial meninges. Now, we always thought that that was happening. Men suffer from migraine, women suffer from migraine. Migraine, however, is female prevalent. Three out of 4 migraine patients are female. So we never really understood what the basis for this female prevalence was. Many, many different factors were suggested, of course, and many different factors have been explored. I mean, obviously, the influence of sex hormones, and that sort of thing has been thought about for a very long time.

But one of the new things that came out in 2020, is that the differences may actually be at the level of the nociceptors themselves, or a difference, not the difference. A difference may be at the level of the nociceptors themselves. So there was a lovely paper by Greg Dussor, from the University of Texas at Dallas, that showed that if we artificially drive nociceptors that innervate the cranial meninges with CGRP, CGRP has been found to be causal in promoting migraine in many patients, not all patients, but in many patients. And when Greg put CGRP onto the dura mater of mice, he found that there was an exaggerated response in female mice compared to male mice. So actually, the female mice were much more sensitive to CGRP than were male mice. This was sort of a new concept and one that started to suggest that there may be really a fundamental difference in the nociceptor itself between males and females.

The second part of that that I think has been supported is that there are other factors that have been revealed to show differences in nociceptors between males and females. One of these has been prolactin. Prolactin is a neuroendocrine substance that's released from the pituitary. It's known for its role in lactation in women, but it has lots of other biological functions. One of the things that is now very clear is that prolactin can produce sensitization of nociceptors. Sensitization means that nociceptors can be activated more readily by stimuli that are normally sub-threshold. In the presence of prolactin, the nociceptors become sensitized, they're more responsive, and that this effective prolactin is profoundly sexually dimorphic. Female nociceptors respond to prolactin far more than male nociceptors. Following sensitization of nociceptors with prolactin, that stimuli, that activate the nociceptor will produce more CGRP releases. So this, the prolactin and the CGRP story may be in fact linked. I think that what emerges from this is that we start to kind of get this idea that there will be male nociceptors and female nociceptors. That's really kind of a new concept. That has not been really explored in any detail in humans. It may be one of the reasons that contribute to this female prevalence of migraine. More women suffer from migraine than men. The pain of migraine may ultimately have to do with activation of nociceptors, female nociceptors may be more sensitive to these sensitizing substances, and so perhaps that could contribute to the female prevalences. So I think that's a new thing in 2020.