FINAL REPORT: Afferent stimulation of the trigeminovascular system produces central sensitization via BDNF signaling in the nucleus caudalis

Published in Pain, August 2016

Read more about the study from UT Dallas.

Summary

Migraine patients are hypersensitive to a variety of sensory stimuli and triggers that don’t affect non-migraineurs.  This suggests that changes within the nervous system are present in migraineurs that allow otherwise normal stimuli to cause pain or provoke attacks. How these changes develop and what mechanisms contribute to the changes is not fully understood.

In our study, we asked whether rats return to normal after they recover from stimulation of the dura with IL-6 (the cytokine interleukin-6) or whether they remain sensitized to otherwise sub-threshold stimuli. We found that they remained sensitized. We went on to investigate a potential mechanism of this sensitivity, focusing on the effects of brain-derived neurotrophic factor (BDNF), a protein known to contribute to changes within the nervous system. We found that if the effects of BDNF were neutralized within the brainstem, the rats were no longer sensitive after recovery from sensitization. Additionally, we could cause sensitization by administering BDNF into the brainstem in the absence of any prior stimulation. Together, these studies show that stimulating the dura with IL-6 causes headache-like responses in rats, and that the sensitization remained even after resolution of this behavior. Further, the sensitized state is dependent on BDNF signaling within the brainstem, implicating this protein in changes to the nervous system that may contribute to migraine.

During our experiments, a study was published (using non-headache pain models) demonstrating that BDNF may be important for changes to the nervous system due to pain in male animals but not in female animals. Since migraine is more common in women, and we were primarily using male rats, we added additional groups of female rats and found that BDNF contributed to sensitization equally in males and females in our migraine-related model. This provided additional support that the mechanism we investigated is also important in females, who make up the majority of migraine patients.

Hypothesis vs Findings

Our findings supported our hypothesis that IL-6 would sensitize the nervous system to later stimuli and that BDNF contributes to this sensitization.

Unanswered questions

We have yet to determine where BDNF originates in the brainstem, as there are several potential sources. We also need to investigate whether stimuli other than IL-6 can cause sensitization using similar BDNF-dependent mechanisms and whether these mechanisms are necessary in models of chronic migraine, where many stimuli are given to animals to produce a state of continual headache. But most importantly, we need to determine how mechanisms downstream of BDNF cause sensitization and whether any of these mechanisms can be exploited for new migraine therapeutics.

What this research means to you

The sensitivity of migraine patients to events that don’t affect those who don’t have migraine argues that changes within the nervous system play a strong role in the pathophysiology of this disorder. MRF funding has helped identify one mechanism by which these changes may occur, through the actions of BDNF within the pain pathway from the dura. Targeting this BDNF mechanism may be a viable approach to not just treat individual attacks but to reverse the nervous system changes that contribute to the repetitive nature of migraine.