Patients often describe pain from the head and face, known as craniofacial pain, as more severe and unpleasant than pain originating from the rest of the body. Some of the most common and disabling chronic pain disorders tend to affect the head and face region. Doctors and researchers have had a poor grasp of why pain coming from these areas can be so much worse.
But now, new animal research led by Fan Wang at Duke University Medical Center in Durham, North Carolina identifies a previously unrecognized neural pathway—that is, a connection between different brain areas—in mice that may explain the heightened response to craniofacial pain.
The pathway connects the trigeminal ganglion (TG), a key brain site involved with facial pain, with the lateral parabrachial nucleus (PBL), a brain region associated with the unpleasant and upsetting aspects of pain.
“The implications of this study are very interesting and potentially explain this long-discussed phenomenon of the differential impact of head pain versus bodily pain,” says Greg Dussor, a migraine researcher at the University of Texas at Dallas who was not involved in the study.
The research was published online November 13th in the journal Nature Neuroscience.
Why all the suffering?
The suffering and emotional burden that accompany many chronic pain conditions is called the affective aspect of pain and is distinct from the sensory “ouch!” component. Two of the most severe chronic pain conditions in terms of patient suffering are trigeminal neuralgia and cluster headaches, both of which affect the head and face region. Why these conditions feature so much pain is largely unknown.
“It was a really naïve question that started this whole research, mainly, could we find a neural circuit for the basis of this increased pain severity? And as we were more focused on the affective aspects of pain we chose to examine the parabrachial nucleus [PBL], a critical relay site for the affective component of pain,” says Wang, referring to this brain structure’s ability to send along electrical signals to different brain areas.
To address this question, the researchers injected a chemical that causes pain to either the hind paw (a body region) or the whisker pad (a facial region) of mice. They found that neurons in the PBL showed more activity when the chemical was injected into the whisker pad, compared to the hind paw.
To understand why, the authors traced the projections of activated neurons in the PBL, that is, they looked to see which areas of the brain these cells connected to. They discovered that the neurons connected to multiple regions in the brain that control emotion and instinctual behavior.
Most importantly, the scientists found, for the first time, a direct connection between neurons in the trigeminal ganglion—the area involved with head and face pain—and neurons in the PBL.
And, by recording the electrical activity of neurons in the PBL, the researchers found that the connection coming from the trigeminal ganglion was excitatory—it promoted pain. At last, here was an explanation for why head and face pain is often more severe and emotionally draining than pain from other areas.
“The head and face regions have all five senses compared to the rest of the body, so biologically speaking there must be a need for rapid, instinctive responses to anything painful to this region,” explains Wang. “The existence of this trigeminal ganglion-to-PBL pathway enables direct access to powerful and heightened emotional responses to help protect these important vital organs in the region.”
Activate or quiet the connection, change the pain
Finally, the researchers studied whether activating the connection between the trigeminal ganglion and the PBL caused aversive behavior in the mice—behavior indicating that the animals found pain unpleasant.
To do so, they gave the mice access to two chambers. In one chamber, the scientists used light to activate the connection between the two brain areas. This is a technique, known as optogenetics, that can be used to either activate or quiet neurons (see related RELIEF interview).
The animals immediately avoided the chamber where they received the light, and also made audible vocalizations when exposed to it. This showed that activation of the trigeminal ganglion-to-PBL pathway caused affective pain-related behaviors.
In contrast, when the scientists used light to quiet the connection, the animals showed fewer pain-related behaviors when the whisker pad was injected with capsaicin (a chemical that makes chili peppers “hot” and that researchers use in their studies to learn more about pain).
Because the head and face regions are responsible for essential functions, experiencing the unpleasantness that accompanies pain coming from these areas may be beneficial in the long run.
“The head is one of the most critical locations in the body and pain originating from it needs to be extremely emotionally disturbing. It might be the case that it also makes the rest of the body hypersensitive to ensure adequate protection,” explains Dussor.
To read about the research in more detail, see the related IASP Pain Research Forum news story here.
Dara Bree is a postdoctoral fellow at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US.