“the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.” Loggia et. al.
Chronic pain was thought for many years to be mostly a neuronal problem. Over or underactive neurons in the spinal cord or neuronal pathways in the brain were creating problems with pain processing – causing an overly robust pain response.
A new player, the microglia, entered the pain field about ten years ago. Among other activities the microglia direct the immune response in the brain and spinal cord. In the past ten years numerous animal studies have incontrovertibly determined that over-active microglia play a critical role in producing chronic pain states.
Studies indicating that a nerve injury causes the microglia to proliferate tremendously suggest that an initial nervous system insult could, in some people, produce a kind of microglial infrastructure for pain and fatigue. By pumping out pro-inflammatory factors that activate pain producing pathways, the microglia could be the spark that keeps the fire, to speak, burning in the brain. Microglial activation by itself is able to induce allodynia in laboratory animals. Animal studies suggest that reducing microglial activation could delay or even prevent the formation of nerve pain.
Despite the great promise that microglial (and astrocyte) activation has shown in helping to explain how chronic pain occurs no one has been able to validate the role they play in producing chronic pain in humans.
The problem has been technological; until recently the technology to detect microglial activation without an autopsy simply wasn’t available. The development of molecules or ligands that bind to proteins associated with microglial (and astrocyte) upregulation is enabling researchers to get a hand on microglial activation. (Astrocytes – a form of glial cell – may be as important as the microglia in the production of chronic pain).
The molecule used in this study – TSPO – is increased in a wide variety of neurological disorders including multiple sclerosis, HIV encephalitis, ischemia and some types of arthritis. TSPO, a microglial inhibitor, is believed to reflect the brain’s attempts to rein in the microglia. Last year we saw Japanese researchers using a different molecule to assess microglial activation in ME/CFS.
Jarred Younger has noted that the technology is not perfect. Last year we saw Japanese researchers using an older version of the same molecule to assess microglial activation in ME/CFS. (They are using the newer molecule in their present study – thanks to Simon McGrath for reporting that). Younger is attempting to use scanning techniques that can assess the degree of neuroinflammation present by measuring the temperature of the brain.)
- Neuroinflammation: Putting the ‘itis’ back into Myalgic Encephalomyelitis – Back to the Future For Chronic Fatigue Syndrome?
In this study – the first of its kind done in humans – U.S. researchers examined microglial activation across the brain and cytokine levels in the blood in nine people with low back pain and nine healthy controls to determine if and where microglial activation might be causing pain.
Evidence for brain glial activation in chronic pain patients Marco L. Loggia,_ Daniel B. Chonde, Oluwaseun Akeju, Grae Arabasz,Ciprian Catana, Robert R. Edwards, Elena Hill, Shirley Hsu, David Izquierdo-Garcia,Ru-Rong Ji, Misha Riley, Ajay D. Wasan, Nicole R. Zurcher, Daniel S. Albrecht, Mark G. Vangel, Bruce R. Rosen, Vitaly Napadow and Jacob M. Hooker BRAIN 2015, doi:10.1093/brain/awu377
“Demonstrating glial activation in chronic pain suggests that these cells may be a therapeutic target, and the consistency with which we found glial activation in chronic pain patients suggests that our results may be an important step towards developing biomarkers for pain conditions,” Marco Loggia
Microglial activation was found most prominently in the thalamus and the somatosensory cortices. Consistently upregulated microglial activity in the thalamus suggested that this important relay center for pain and other sensory signals played a particularly prominent role in the production of chronic pain.
The Japanese research effort found evidence of neuroinflammation in ME/CFS in several of the same brain regions ( cingulate cortex, thalamus) plus some new ones ( hippocampus, amygdala, midbrain, and pons). With microglial activation in the thalamus associated with reduced cognition and increased pain in ME/CFS, inflammation in the thalamus may play an important role in both ME/CFS and low back pain.
One study has found increased thalamic activity in ME/CFS and depressed patients with ME/CFS patients demonstrated more thalamic activity. Several studies suggest the thalamus may play a role in fibromyalgia as well.
Other areas of increased microglial activation included a variety of brain regions often associated with ME/CFS and fibromyalgia including the insula, prefrontal cortex, cingulate cortices, the supplementary motor area and the basal ganglia.
“By showing that levels of an inflammation-linked protein are elevated in regions known to be involved in the transmission of pain, the study … paves the way for the exploration of potential new treatment strategies and identifies a possible way around one of the most frustrating limitations in the study and treatment of chronic pain — the lack of an objective way to measure the presence or intensity of pain.” Mass General Hospital
The authors – from Harvard and Duke Universities – asserted that now that microglial activation has been associated with chronic pain production in human that clinical trials of microglial inhibitors should begin immediately. Known microglial inhibitors have been FDA approved for other conditions.
The first drug they pointed to, interestingly enough, was none other than low dose naltrexone, a known glial cell inhibitor that two Younger studies have shown can reduce pain in fibromyalgia. They noted that two other putative microglial inhibitors (propentophylline, minocycline) have not panned out in two chronic pain trials but, pointing out that it’s easier to prevent microglial activation than knock it out, they asserted that the trials may have been too short (8 days to 4 weeks) to show efficacy.
This study should start the ball rolling on increased efforts to reduce chronic pain by reducing microglial activation. A surprising finding that the patients with the highest TSPO levels had reduced pain added TSPO enhancing drugs to the list of new possibilities for reducing pain. Younger’s Neuroinflammation, Pain and Fatigue Lab is currently testing how effective botanicals are at reducing microglial activation in Gulf War Syndrome. Younger has elicited some surprise at how effective some of the botanicals may be. (Subscribe to his newsletter for updates).
More on Possible Microglial Inhibitors
- Check out a long list of putative microglial inhibitors
- New Chronic Fatigue Syndrome and Fibromyalgia Lab Opens: Jarred Younger Talks
- Palmitoylethanolamide (PEA) – A Medical Food for Fibromyalgia and (ME/CFS)?
- Drug Repurposing I: Antibiotics to Reduce Microglial Activation in ME/CFS and Fibromyalgia?
The microglial field – already a hot one – should heat up more now that pain has been linked in human studies to microglial activation.
Many labs are engaged in finding ways to accurately assess microglial activation and neuroinflammation. At least three studies testing marker of microglial activation (GEH120714 (18F)), ([18F]DPA-714), [C11]PK-1195 PET) are underway. Ultimately scanning techniques should be able to pinpoint patients for whom reducing neuroinflammation makes sense.
The authors asserted that treatment trials using microglial inhibitors should begin now. Only minocycline, however, shows up in a search of the Clinical Trials database. As noted earlier, Younger is examining the efficacy of botanicals in a Gulf War Illness study.
With microglial inhibition, Dr. Pridgen’s antiviral approach to Fibromyalgia, immune therapies and brain stimulation all on the table now, researchers are getting more creative in their approach to reducing chronic pain.
- Drug Combo in Pridgen Antiviral Fibromyalgia Trial Identified
- Symposium Calls For Use of Immunotherapy To Treat Chronic Pain
Keep the Information Flowing
After years of work it’s time to attempt what we’ve never been able to do before – get Congress to force the NIH to double its funding for ME/CFS. Support the historic bill to increase research funding, add new ME/CFS research centers, require the development of a strategic plan, etc.. It will take less than 5 minutes.