Pain has a big “ouch” component—put simply, it hurts. This is known as the sensory aspect of pain, and in conditions like migraine headache, additional sensory changes are present too, such as increased sensitivity to light and sound.
But pain can also be an incredibly unpleasant experience, which is often referred to as the aversive, or emotional, component of pain. However, while the sensory features of headache pain have been examined closely in recent years, the unpleasantness of this condition has been more difficult to study in animals.
Recent research addresses this gap in knowledge by identifying a brain circuit that controls headache pain aversiveness, using a headache model in rats.
Maggie Waung, University of California, San Francisco (UCSF), US, along with Howard Fields and colleagues at UCSF, show that headache activates a neural circuit between two brain regions. One of these regions is the ventrolateral periaqueductal gray (vlPAG), an area known to modulate pain. The other is the ventral tegmental area (VTA), a vital part of the brain’s reward system.
What’s more, quieting the activity of the newly-identified circuit relieved the aversiveness of headache, in the animal model.
“The value of this study is that it demonstrates it’s the aversive qualities of migraine pain that are being modulated by this circuit, not the sensory qualities of that pain,” said Frank Porreca, University of Arizona, Tucson, US.
“The authors showed that there is an important aspect of migraine pain that, historically, has been overlooked but is deserving of our attention in the future as we try to understand more about what causes migraines,” continued Porreca, who studies migraine but was not involved with the new study.
The research was published September 10, 2019 in the journal Cell Reports.
A model of headache
The understanding of migraine has changed fairly dramatically in recent years, with the brain now taking center stage. Indeed, Waung said that symptoms including sensitivity to sound, light and smell points to a common neurological process in people who suffer from migraines (known as migraineurs).
“In medical school, I was taught that migraine was due to changes in cerebral blood vessels,” said Waung. “But once I became a neurologist, and spoke to more patients who had chronic headaches, it became clear to me that migraine is a disorder of the brain and how the brain processes stimuli. To better understand what might be triggering these headaches, we needed to take a brain circuit approach,” she continued, referring to the neural connections between different brain regions.
After first establishing that nerve fibers from the vlPAG make direct connections to the VTA, the researchers turned a rat model of headache to learn why those connections might be important for headache pain.
In this case, the group created a headache model in which they applied substances that cause inflammation right onto the dura, one of the membranes that surrounds the brain. The dura also contains pain-sensing neurons that respond to such substances.
This model mimics headache, including some of the features of migraine, such as allodynia, a phenomenon where things that aren’t ordinarily painful, such as a gentle touch of the skin, become extremely painful, as well as increased sensitivity to sound.
Also seen in this headache model is an increase in the amount of c-Fos in areas of the brain known to be involved in headache. c-Fos is a protein that serves as an indirect measure of the activity of nerve cells—the more c-Fos, the greater the activity of the cells.
Let there be light
Now the stage was set to learn more about the direct connection between the vlPAG and the VTA and whether it actually mattered in terms of how the animals behaved.
The team discovered that neurons in the vlPAG from animals receiving the inflammatory substances on the dura contained more c-Fos, compared to control animals who only received a harmless saline solution. A significant number of these neurons in the vlPAG connected to the VTA. These results told the researchers that the circuit between the two brain regions was active.
To understand what that meant for the behavior of the animals, the researchers used optogenetics. This is a common experimental technique in the field of neuroscience where light-sensitive proteins are inserted into specific nerve cells. This gives scientists the opportunity to activate or inhibit the cells using light. In the current study, the researchers used optogenetics to manipulate the activity of nerve fibers projecting from the vlPAG to the VTA.
First, they used rats whose nerve fibers would become activated in response to light. These otherwise healthy animals were placed into a chamber where they were exposed to light on one side of the chamber. It turned out that the animals avoided the lighted side of the chamber, showing a clear preference for the side not exposed to light. This showed that activating the vlPAG-VTA circuit was aversive to the animals, in the absence of headache.
But what about the animal model of headache? Here, the animals that had received the inflammatory substances to cause headache were also placed in the chamber. But this time, the researchers used light to quiet the activity of the nerve fibers going from the vlPAG to the VTA.
In this case, the animals preferred the lighted side of the chamber, whereas control animals that had received a harmless saline injection showed no preference. This showed that turning off the vlPAG-VTA circuit eased the aversiveness of headache.
So what is the relevance of the findings for people with migraine? Waung said the results could one day lead to better treatments.
“While the PAG has an important role in decreasing pain, we often ignore the role it might play in exacerbating pain, and, when you put it all together, it does make sense. This provides us a potential circuit to target for future migraine therapies,” Waung said, referring to the possibility that drugs could potentially be developed that change the activity of the circuit.
This news article is a plain language summary of a story that first appeared on the IASP Pain Research Forum.
Kayt Sukel is a freelance writer based outside Houston, Texas.