Immune System Involvement in Chronic pain
By Dr John Quintner, Rheumatologist
Member of the Chronic Pain Australia National Advisory Panel
What is the Immune System?
The immune system is made up of a complex network of specialized cells (fibroblasts, macrophages, lymphocytes etc.) and lymphoid organs (such as the spleen and lymph glands) that appear to monitor the state of health of tissue cells, both those close by and those at a distance.
Importantly, cells of the immune system also reside within the central nervous system in close contact with neural transmission cells. They are known as glial cells (the name derived is from the word “glue”) and include both astrocytes and microglial elements. Cells with similar function reside within peripheral nerves.
What is its role in bodily function?
The immune system defends the body against infection by agents such as bacteria, viruses, fungi and parasites. It does so by recognising, neutralising, and killing these foreign substances, which have the potential to damage tissue cells. It also plays an important part in defending the body against invading tumour cells.
Immunologists tend to use such dramatic terms as “attack,” “defence,” and “invaders,” as if boundaries are being contested and the body becomes the localized site of battle between self and non-self or other.
However, it is now understood that the immune network forms intricate structural and functional relationships with the brain. There is continuous two-way communication between the brain and the immune system, which coordinates the body’s response to stressors such as trauma, infection and inflammation.
What is its role in chronic pain?
When cells of the immune network are activated, they produce molecules known as pro-inflammatory cytokines (IL-1a, IL-1b and TNF-a) as well as many other important substances (i.e. neurotransmitters and neuropeptides).
Cytokines (cell messenger molecules) released from within the peripheral tissues can act upon special circuits in the brain, either by stimulating the sensory nerves at the site of tissue damage, or by being transported into the brain via the blood stream.
In response to these peripheral signals, the glial cells become active. In turn, they release pro-inflammatory cytokines, which can render the nearby nerve cells more sensitive to all input. This process seems to contribute to the state known as central sensitisation, whereby the nervous system becomes hyper-responsive to stimulation.
Glial activation and cytokine release can also be triggered by nervous system infections and injury, as well as by the prolonged use of high dose morphine. The development of opioid tolerance and opioid-induced hypersensitivity can be at least in part explained by such glial activation.
The same cytokines activate the hypothalamic-pituitary-adrenal axis, resulting in an increase in circulating cortisone. This process tends to damp down the activity of immune cells and the manufacture of pro-inflammatory cytokines.
However, cytokine release can also cause fever, and many non-specific behavioural responses such as, malaise, fatigue, sleepiness, loss of appetite, loss of libido (sex drive), social withdrawal, irritability and hyperalgesia. These are the important components of the extended sickness or stress response, which is an inbuilt core process shared by all members of the animal kingdom.
Incidentally, this same process of cytokine release may explain many of the clinical features of the puzzling pain condition known as fibromyalgia syndrome, of which hyperalgesia (an umbrella term for the phenomenon of increased pain sensitivity) is such a prominent feature. Given that there appear to be many possible triggers for this condition, the focus for research needs to be directed towards understanding how a self-regulatory process may be disturbed in these patients.
What are the implications for people in pain?
Data from experimental animal studies suggest that glial activation may potentially be powerfully modulating pain in human chronic pain states as well. The main implication for pain sufferers is the exciting possibility that drugs which target glia can either prevent their activation in the first place or “calm them down” when they are activated, causing them to revert to their quiescent basal state. Not only will their pain come under better control, it is hoped that major problems such as opioid tolerance and dependence will be prevented. Trials of such drugs are currently underway.
References:
Dantzer R, Kelley KW. Twenty years research on cytokine-induced sickness behavior. Brain, Behavior & Immunity 2007; 21: 153-160.
Watkins LR, Hutchinson MR, Ledeboer A, Wiesler-Frank J, Milligan ED, Maier SF. Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids. Brain, Behavior & Immunity 2007; 21: 131-146.