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The Immune System and Pain
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There is a whole new way of thinking of about pain that has nothing to do with pain being
transmitted by nerve cells in well defined nerve pathways.
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In the last few years, we have learned it has to do with activation of glia and the immune system.
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Pain is a central neuroimmune activation.
There is close interaction of nerve pathways and the central immune system.
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Neuroimmune responses parallel but do not always mirror peripheral immune responses.
The differences are critical.
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The science of understanding immune cell-glia and glia-neuronal interactions is in its infancy.
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What are glia?
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Glia are cells in the central nervous system (CNS), the brain and spinal cord. Ninety percent of the cells in the CNS are glia – microglia, astrocytes, oligodendroglia, perivascular glia. Glia outnumber neurons by almost 10 to 1.
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Microglia and astrocytes are immune cells that can release inflammatory responses with harmful effects on nerve cells such as inflammation, toxicity, and excitability. However, scientists are beginning to show that activation may also lead to good outcomes that are helpful for nearby glia and neurons, protecting against inflammation, toxicity and restoring normal pain signaling. In other words, they can restore balance.
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Beneficial and pathological microglia
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Neuroinflammation is a normal and necessary process in the acute phase, but not when it takes on a life of its own and creates persistent pain or disease directed against normal tissue (autoimmune response). They may fail to release protective agents (e.g. BDNF, Brain-Derived Neurotrophic Factor).
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Neuron-glia Tetrapartite Synapse
Glial activation from pro-inflammatory to anti-inflammatory state
(click image to enlarge)
Image from Milligan, E, Watkins, L. Pathological and Protective Roles of Glia in Chronic Pain,
Nature Reviews 10:23-36 (2009)
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Neuroinflammatory Disorders
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There is an growing body of evidence that shows many diverse diseases are characterized by neuroinflammation, such as Alzheimers, Parkinson’s Disease, ALS, Multiple Sclerosis, neuromuscular and myofascial syndromes and neuropathic pain, fibromyalgia, and chronic fatigue syndrome. There are research plans to show activation of glia in other conditions: Tourette’s Syndrome, dystonia, blepharospasm, and torticollis. A neuronal model no longer works to explain these conditions.
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What the heck is microglial activation and priming?
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How do glia become activated? They are always active, not activated but active, surveying their environment. Something must occur for them to become activated. Similar to a bee sting that primes your immune system, the first bee sting will not kill the person who is allergic, but BOOM! the second sting can kill. Glia can become primed by a first pain, but when pain next occurs, glia become activated and they respond faster, harder, longer.
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When activated, they change shape like amoeba and migrate to the site of injury or infection or stroke or dead cells where they proliferate, release cytokines, and phagocytose (consume) targets such as virus, dead tissue, important in wound healing. Microglia and astrocytes can release neuroexcitatory and pro-inflammatory products and growth factors for pain and hyperalgesia. See links to several recent publications on glia here, and mechanisms here and here. Microglia can repair the CNS. Or, an injury may heal and be long gone, but chronic pain may persist for years. How do we turn it off? The signal is no longer telling us about a new danger.
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The goal of research is to find ways to interact with the cascades of pro-inflammatory molecules and receptors to restore balance in the system. This is a major paradigm shift in treatment of chronic pain that has already led to many insights. Refer articles here.
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Toll Like Receptors
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Like all immune competent cells, glia have a myriad of receptors on their cell surface membranes. One of the more important are the Toll Like Receptors (TLRs) that are innate immune receptors in the CNS, discussed here. See image, below. TLRs “are key regulators of both innate and adaptive immune responses. The function of TLRs in various human diseases has been investigated….These studies have shown that TLR function affects several diseases, including sepsis, immunodeficiencies, atherosclerosis and asthma…. [They] may contribute to susceptibility to severe neonatal inflammatory diseases, allergies, and autoimmune diseases.” Other studies have shown “Toll-like receptors (TLRs) are essential in the host defense against infections. They also have functional roles in tumor progression and their ligands affect tumor cell proliferation, anti-apoptosis and immune escape. The expression or up-regulation of TLRs has been detected in various tumor cells.” “Dysregulation of these signaling pathways has severe consequences, and causes many autoimmune diseases and chronic pathological inflammation.”
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The Toll Like Receptors are not like other receptors. Not these snug little pockets where naltrexone binds. Instead the Toll Like Receptors are like an entire football field, with enormous nooks and crannies. Unlike other receptors, they have enormous interactions with many molecules and medications, e.g. naltrexone is a TLR4 inhibitor, an immune modulator, amitriptyline is a TLR4 inhibitor. And “Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression.” That source is referenced here. Opioids create pain, not just the dread opioid induced hyperalgesia. Glia also contain cannabinoid receptors. Glia produce endogenous cannabinoids and they inactivate them.
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Toll-Like Receptors.
(Image courtesy of SABiosciences, click to enlarge)
Their action on IL-10 is key and more on that will be posted here later.
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Antibodies for pain?
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Some pain syndromes have been found to produce distinct antibodies.
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There is small but growing evidence that the immune system plays a role in Complex Regional Pain Syndrome, CRPS. These individuals have inflammatory markers in spinal fluid and tissue fluids. Recent studies have found antibodies against nervous system structures, specifically, “autoantibodies against an inducible autonomic nervous system autoantigen” in 30 to 40% of persons with CRPS.
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In 2010, a small study found that intravenous immunoglobulin (IVIG) can provide relief in a tiny percentage of patients. IVIG potentially interferes with those autoantibodies and reduces, i.e. downregulates, the inflammatory cytokines that are important in mechanisms of pain and hyperalgesia in the brain and the body. This study has many limitations but it is a first for IVIG.
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JJ Van Hilten et al have found HLA antigens associated with Complex Regional Pain Syndrome with fixed dystonia. “Our results encourage future studies to evaluate the role of HLA-B62 and HLA-DQ8 in different subtypes of CRPS.” This gene family has important immunologic functions.
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And, epidemiology studies show that persons with CRPS are more likely to have asthma.
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The study of glia is in its infancy but it is growing rapidly in many directions. There are drugs that can distinguish activated glia for targeted treatment, new methods of visualizing glia, new sites for pharmacologic intervention, and nanotechnology to deliver medication directly to the inflammation. ` More will come provided there is philanthropic support for this work. It is heartbreaking that NIH contributes less than half of 1% of its research dollar to pain.
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My thanks to the Reflex Sympathetic Dystrophy Syndrome Association, RSDSA.org, for sponsoring a workshop on Glia and Neuroinflammation that brought together the world’s foremost scientists and provided a unique forum for them to interact and learn from each other.
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It is hoped that their next workshop this year will be on imaging glia. We need to extend the work that has barely begun.`
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The material on this site is for informational purposes only.
It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.
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For My Home Page, click here: Welcome to my Weblog on Pain Management!
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04/15/2011 at 9:09 pm
Very interesting. I speak from experience when I say thay I agree that “opiates create pain”. I’m posting about your article today.
04/18/2011 at 9:23 pm
Please add your experience on that.
04/16/2011 at 12:49 am
It is certain that developing our understanding of the role of the immune system and it’s interaction with the nervous and endocrine systems will help design treatment. This is true for both pharmacological manipulation of our chemistry and how we can design rehabilitation programmes. The latter is my concern and how we can influence all of these systems through good patient education to reduce fear and anxiety, choose exercises that do not provoke an ill-response. This is by creating the right context, environment, understanding, timing and intensity. Dr Mick Thacker at King’s College London is the main proponent behind the notion of ‘movement as an antigen’ that is both highly applicable clinically and fascinating. It is this kind of thinking that is really driving forward our approaches and ability to be increasingly optimistic.
04/18/2011 at 9:42 pm
Interesting concept: Movement as an antigen. Please cite articles. I would like to know more.
The role of exercise and health is certainly recognized as influencing neuroplasticity.
Exercise triggers BDNF – Brain Derived Neurotrophic Factor – which is believed to be why exercise reduces the progression of Alzheimer’s Disease. BDNF is involved in learning and memory.
Not all exercise is equal.
A recent one year study of a group aged 55 to 80 showed that walking 40 minutes three times a week improved memory and increased brain size when compared to a group that did stretching and aerobics for an equal amount of time. Of course, ideally we would like our bodies to be able to stretch, do aerobics and walk. But the memory function seems to be specific.
I’ve also posted on exercise as a natural pain reliever here. Even 10 minutes a day can help.
I do not know much about timing and function of glia or the immune system, but neuropathic pain is typically worse at night.
Timing is controlled by the central pacemaker, the suprachiasmatic nucleus in the hypothalamus. When I did research in chronophysiology and epilepsy in 1981, we knew of more than 1,000 cycles in the human body. Light is the most important cue to entrain cycles in plants and animals. Oncologists are beginning to look at timing of chemotherapy. Chronomodulated delivery schedules have led to improved tolerability and/or better antitumor activity as shown in randomized multicenter studies in over 40 institutions in 12 countries noted in 2002 here.
Perhaps someday we will figure out better timing of interventions for pain.