FINAL REPORT: The Effect of the CGRP Receptor Antagonist (MK-8825) on the Response to Trigeminal Nociception and Pro-inflammatory Cytokine Release

Published in Headache, Volume 53, Issue 1, January 2013

Published in Experimental Neurology, September 2015

Summary

Calcitonin-gene-related peptide (CGRP) plays a crucial role in migraine and in the processes of peripheral and central sensitization of the trigeminal system. CGRP is a potent vasodilator and a major contributor in the process of neurogenic inflammation, facilitating pain transmission leading to allodynia and hyperalgesia, clinical characteristics not only in migraine but in inflammatory and neuropathic pain conditions.

In this study, we developed and characterized a novel mouse model of acute orofacial pain. Using this model, we investigated the effects of a potent and selective CGRP receptor antagonist with good oral activity in rats on quantifiable nociceptive behaviors (grooming patterns), trigeminal nucleus caudalis (TNC) activation and cytokine release.

Hypothesis vs. Findings

We developed a mouse model of trigeminal pain, where inflammatory pain in the orofacial region is induced. Then we characterized acute nociceptive behaviors that mice exhibit consistent with TNC activation. We hypothesized that treatment with a CGRP receptor antagonist would decrease the nociceptive behaviors, TNC activation, and pro-inflammatory cytokine release in this model. Our findings indeed demonstrated that mice receiving the CGRP receptor antagonist exhibited a decrease in nociceptive behaviors and a decrease in TNC Fos immunoreactivity at 2 and 24 hours after the treatment, but did not alter pro-inflammatory cytokine release.

Unanswered Questions

We were able to show that blocking CGRP receptors decreased nociceptive behaviors and TNC activation but did not decrease cytokine release at 2 and 24 hours. A single dosage of the antagonist did not seem to have an anti-inflammatory effect. As this was an acute pain study (2-24hrs), one unanswered question is whether repetitive dosing would decrease pro-inflammatory cytokine release in our model. An additional question is whether blocking CGRP receptors in a chronic pain model would decrease pro-inflammatory cytokine release and therefore have an anti-inflammatory effect.

What This Research Means to You

Our study has provided new insights into the role of CGRP in acute trigeminal nociception in the orofacial region in a new in vivo model. The development of CGRP receptor antagonists represents not only an exciting new potential therapy for migraine, but also an important tool to advance our understanding of the trigeminovascular system pathophysiology.

Learn More

MRF has named Dr. Marcela Romero-Reyes as the first recipient of the Thomas E. Heftler Migraine Research Award. The award was established to recognize and encourage emerging talent in the field. Dr. Romero-Reyes has turned a lifelong interest in science into a promising career researching and treating orofacial pain, the emerging dental specialty concerned with the diagnosis and management of pain in the trigeminal nerve system, which is also thought to play a vital role in migraines.

Dr. Romero-Reyes entered medical school in her native Mexico, but later transferred to dental school. While still a student, she developed an interest in orofacial pain after treating patients suffering from trigeminal neuralgia, a chronic pain condition that causes extreme facial pain. She found this specialty appealing because it allowed her to focus on the medical and diagnostic aspects of dentistry. After finishing dental school, Dr. Romero-Reyes moved to Los Angeles to complete a PhD and post-doctoral fellowship at UCLA.

Dr. Romero-Reyes recently accepted a tenure-track faculty position in NYU’s orofacial pain program, where she will conduct research in her own lab. Supported in part by the Heftler Award, she will use a new model to study how CGRP receptor antagonists modulate pain in mice. The goal of this research is to expand the understanding of CGRP’s role, and hopefully lead to the development of new preventive migraine treatments. In addition to her research, Dr. Romero-Reyes will teach neurophysiology to medical and dental students and treat patients. She is thrilled that her new position will allow her to do all of these things, as she believes working with patients informs and motivates her research.

Dr. Romero-Reyes considers it a “privilege” to receive the Heftler Award from MRF and is thrilled that the scientific community sees value in her research. She is passionate about research and truly hopes that she will make a contribution to the treatment of migraine and other orofacial pain disorders. One of her favorite things about being a scientist is traveling to conferences to present her findings.  Dr. Romero-Reyes encourages young scientists in all fields to remain positive and to “never lose their drive to do good things.”

Dr. Romero Reyes thinks it is important for scientists to maintain balance in their lives. Her own passion for science extends beyond her laboratory. She is interested in physics, anthropology and astronomy, and is planning to purchase a new telescope so that she can continue her stargazing hobby. She is also a talented fencer.