Surprise, Surprise: Pain-Sensing Neurons Do Not Appear to Drive Chronic Inflammatory Pain

Neuron

Researchers are making progress towards understanding how acute pain becomes chronic. Image credit: eraxion/123RF Stock Photo

Acute pain serves as a powerful warning signal. It helps us to avoid damage to our bodies that might occur, for instance, while touching a hot stove or stepping on a piece of broken glass. But with chronic pain, the nervous system sounds an ongoing alarm even when danger has passed.

Researchers are working to understand how acute pain becomes chronic, and which cells are responsible for the transition. Pain-sensing sensory neurons, the cells that sense threats and send pain signals from the body towards the central nervous system (brain and spinal cord) with their electrical activity, are a prime suspect. However, new research now shows that these cells may not drive one type of chronic pain—chronic inflammatory pain—after all.

The work was published online February 8 in the journal eNeuro.

In order to study the pain system in mice and rats, investigators sometimes inject animals with substances that cause inflammation, resulting in pain. Most studies of inflammatory pain test animals just a day or two after injection, but the short-term nature of this approach may not be relevant to understanding chronic pain conditions in people, which can last for years.

Consequently, in the new study, lead researcher Cheryl Stucky and colleagues at the Medical College of Wisconsin, Milwaukee, US, followed animals over the course of eight weeks after injection, a longer time frame that might more closely model chronic pain.

“If you want to understand chronic pain, you need to use a chronic model. Acute models are fine for acute pain, but that’s not modeling chronic pain,” Stucky says.

Eight weeks after the researchers injected mice in the hindpaw with a cocktail of substances to spur inflammation, the animals still displayed behaviors indicating pain. But, unexpectedly, the sensory neurons were less active, rather than more active, in the chronically inflamed animals, compared to control mice.

The finding has two important implications. First, sensory neuron hyperactivity does not appear to drive chronic inflammatory pain in this specific animal model. Thus some other mechanism must be responsible. Second, the activity of the sensory neurons is somehow dampened down, perhaps as a protective measure against damage—to the sensory neurons themselves or to spinal cord neurons—that could result from a constant barrage of activity.

Which cells inhibit the sensory neurons remains an open question, with many possible answers. Immune cells in the skin, skin cells, and sensory neurons themselves might all make substances that influence nerve cell signaling. Different neurons in the spinal cord or brain might also affect the activity of sensory neurons.

If the sensory neurons themselves are not driving chronic pain, then what is? The researchers hypothesize that changes in the spinal cord, brainstem and higher brain centers may be the culprits instead.

The young and the old
Chronic pain is more likely to occur in the elderly than in young people, and so it makes sense to study pain in older mice, increasing the chances that results from animal studies will have more relevance to older people with pain. The researchers did experiments comparing two-month-old mice—the rough equivalent of 17-year-old humans—with mice over 18 months old, which corresponds to humans over age 67.

When the investigators measured pain and nerve cell activity in response to painful pokes to the animals’ paws with thin filaments (another technique commonly used in pain studies), they found that pain-free, old mice were more sensitive than were young mice. But after the inflammatory injection, young mice reacted to both acute and chronic inflammatory pain more dramatically than aged mice.

The researchers concluded that, in young mice, the nervous system might be more malleable in response to pain, but that older mice might have a higher level of baseline inflammation, so that additional inflammation may not have as great an impact as it does in young mice. Changes in the immune system with age might contribute to the discrepancy.

It is important to recognize that the current results come from one type of pain model—chronic inflammatory pain—used to study pain in animals. Thus the current findings may not necessarily apply to different types of chronic pain, such as that caused by nerve injury, called neuropathic pain.

In addition, each chronic pain condition probably depends on communication between different types of cells, using different chemical signals in multiple locations, and these may vary over time. Researchers face an enormous challenge in identifying all of these factors, particularly because animal models of pain cannot perfectly mimic human pain conditions.

Still, the findings reveal a novel pain-signaling phenomenon that warrants further investigation in other pain conditions.
—Stephani Sutherland

To read about the new research in more detail, see the related Pain Research Forum news story here.

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance journalist in Southern California. Find her at StephaniSutherland.com or on Twitter @SutherlandPhD