The New York Times writes on a significant advance in understanding the origins of otherwise unexplained chronic pain. In short, experts now believe that most kinds of unexplained chronic pain are caused by glial cells that malfunction. Those cells are complex in their functions and their ability to do the same things, e.g., foster feelings of unexplained pain, by multiple pathways. Glial cells are found in the nervous system in close, complex association with neurons. Glia help neurons function properly and they carry food to neurons and waste away. They are believed to have much more impact on neuron signaling than was believed just a few decades ago.
This finding tells researchers to increase their focus on glial cells, which have not been studied nearly as much as neurons. That's the good news. The bad news is that even if a drug is found that targets and shuts down one pathway that glial cells use to create feelings of pain, they can use other pathways to generate pain.
There are six main kinds of glial cells as shown in the diagrams below, four in the central nervous system (brain and spinal cord) and two in the peripheral nervous system (everywhere else), and subsets of at least one of those main kinds are being found and described[1]:
The NYT writes:
Although glia are scattered throughout the nervous system and take up almost half its space, they long received far less scientific attention than neurons, which do the majority of signaling in the brain and body. Some types of glia resemble neurons, with roughly starfish-like bodies, while others look like structures built with Erector sets, their long, straight structural parts joined at nodes.
When first discovered in the mid-1800s, glia — from the Greek word for glue — were thought to be just connective tissue holding neurons together. Later they were rebranded as the nervous system’s janitorial staff, as they were found to feed neurons, clean up their waste and take out their dead. In the 1990s they were likened to secretarial staff when it was discovered they also help neurons communicate. Research over the past 20 years, however, has shown that glia don’t just support and respond to neuronal activity like pain signals — they often direct it, with enormous consequences for chronic pain.
If you’re hearing this for the first time and you’re one of the billion-plus people on Earth who suffer from chronic pain (meaning pain lasting beyond three to six months that has no apparent cause or has become independent of the injury or illness that caused it), you might be tempted to say that your glia are botching their pain-management job.
And you’d be right. For in chronic pain, researchers now believe, glia drive a healthy pain network into a dysregulated state, sending false and destructive pain signals that never end. Pain then becomes not a warning of harm, but a source of it; not a symptom, but, as Stanford pain researcher Elliot Krane puts it, “its own disease.”
It is still the case that we know far less than what we don't know. And, in the way science understood glial cells since the mid-1800s reflects human nature and the scientific method. Humans, including scientists, are biased to look at what appears to be the coolest, most important stuff and to ignore or even downplay the significance of what initially appears to be dull or even "junk," such as in junk DNA which was originally thought to have little or no function.
Just look at how human perceptions of glial cells progressed: glue → janitorial staff → secretarial staff → middle level management, or something about like that. It took about 170 years for that mental progression or understanding to occur. Notice how the perception of researchers is still trapped by the implicit human perception of neurons as the top of the heap, i.e., they are the CEO and Chairman of the board? The question now is, can glia rise above middle level management to senior management status? More research will reveal that answer, preferably sooner than later.
Question: Is this way cool or what, even if a chronic pain cure isn't on the horizon yet?
Footnote:
1. Glial cell subpopulation research is in early days. A 2020 paper in Nature Communications, Identification of region-specific astrocyte subtypes at single cell resolution, included this:
1. Glial cell subpopulation research is in early days. A 2020 paper in Nature Communications, Identification of region-specific astrocyte subtypes at single cell resolution, included this:
Astrocytes, a major cell type found throughout the central nervous system, have general roles in the modulation of synapse formation and synaptic transmission, blood–brain barrier formation, and regulation of blood flow, as well as metabolic support of other brain resident cells. Crucially, emerging evidence shows specific adaptations and astrocyte-encoded functions in regions, such as the spinal cord and cerebellum. To investigate the true extent of astrocyte molecular diversity across forebrain regions, we used single-cell RNA sequencing. Our analysis identifies five transcriptomically distinct astrocyte subtypes in adult mouse cortex and hippocampus. Validation of our data in situ reveals distinct spatial positioning of defined subtypes, reflecting the distribution of morphologically and physiologically distinct astrocyte populations. Our findings are evidence for specialized astrocyte subtypes between and within brain regions. The data are available through an online database (https://holt-sc.glialab.org/), providing a resource on which to base explorations of local astrocyte diversity and function in the brain.
In this research, bits of DNA with fluorescent dye attached was used to visualize individual astrocytes in fluorescent light under a microscope and to differentiate one subtype from another using different dies that fluoresce in different colors, i.e., at different wavelengths.
