Gone are the days when scientists believed that the body’s immune and central nervous systems operated independently. Recent studies have shown that certain immune system cells play a role in a key function of the nervous system: the activation of pain, especially neuropathic pain.
Unlike “nociceptive” pain, which is caused by injuries that stimulate pain receptors, neuropathic pain results from injury to or malfunction of the peripheral nervous system. This type of pain, which is associated with a burning, shooting sensation and is frequently chronic, is often triggered by an injury, even though the injury may not involve damage to the central nervous system. Neuropathic pain, which is common among patients with cancer, diabetics with peripheral neuropathy, and shingles patients suffering from post-herpetic neuralgia, does not respond well to treatment with opioids, a major class of drugs used to treat moderate to severe pain.
“The emerging story is that the pain pathway can no longer be envisioned as a simple chain of neurons,” says Linda R. Watkins of the Center for Neuroscience at the University of Colorado at Boulder. “Rather, microglia and astrocytes [small cells that are scattered throughout the nervous system] can dramatically amplify neuronal signaling, thereby creating pathological pain. These glia become activated by immune challenges and substances released by neurons. Upon activation, glia release an array of substances that lead to amplification of pain. Of these, proinflammatory cytokines appear to be common spinal mediators of pain.”
Cytokines are small proteins secreted by the immune system that are important in controlling local and systemic inflammatory responses. Substances released by cytokines stimulate peripheral nerves, signaling the brain and spinal cord that inflammation has occurred. In turn, this peripheral inflammation leads to the synthesis and release of cytokines in the brain and spinal cord. This communication between the brain, spinal cord and peripheral nerves is evidence, researchers say, of the impact of immune activation on pain.
Allan Basbaum, a pain researcher at the University of California, San Francisco, says that while targeting cytokines in pain activation is not new, “what is new is the specification of the targeting, which might be ideal for treating neuropathic pain.”
In a study published in the Proceedings of the National Academy of Sciences in April, Dartmouth researchers, led by neuropharmacologist Joyce DeLeo, showed that an immune receptor in the central nervous system called toll-like receptor 4 (TLR4), which is expressed in microglia after nerve injury, plays a role in triggering neuropathic pain. Microglia, the smallest of the glial cells, are highly mobile cells that play an important role in protecting the nervous system.
The researchers manipulated a nerve in the lower back of TLR4-deficient mice and assessed how the mice responded when exposed to heat or touch. The team found that hypersensitivity was reduced and cytokine expression decreased. The results, they say, show that TLR4 initiates a nervous system immune response, which leads to a release of cytokines and hypersensitivity to touch and temperature— hallmarks of neuropathic pain. They suggest that blocking the action of this receptor could help alleviate chronic pain caused by nerve damage.
Cytokines, such as those being produced by white blood cells in this image, are immune system proteins that also play a role in neuropathic pain. © NANCY KEDERSHA / Science Photo Library
Other studies also have shown how targeting certain cytokines may be effective in treating neuropathic pain. Scientists at Merck Research Laboratories found that blocking a receptor called chemotactic cytokine receptor 2, which is involved in inflammation, might provide effective treatment for both inflammatory and neuropathic pain. Watkins and her team at the University of Colorado discovered that a gene therapy approach using interleukin-10, an anti-inflammatory cytokine, is an alternative to drugs that target neurons to control pain.
In addition, DeLeo has developed a model that allows an immune activator to be injected near a single healthy peripheral nerve in rats. This has allowed researchers to examine the mechanisms underlying pain at the site of the immune activation, within the peripheral nerve, and in the spinal cord.
Researchers are now focusing on whether pharmacological intervention at the peripheral nerve and spinal cord can help prevent or reverse immune-induced pain.
“Pathological pain is managed poorly, if at all, by currently available drugs,” says Watkins. “The involvement of glia in exaggerated pain responses is exciting because it predicts new approaches for the control of human pathological pain. It predicts that preventing glial activation or the action of unique glial products such as proinflammatory cytokines may provide a solution for the devastating effects of human pathological pain.”
Although animal studies have already identified several compounds for controlling neuropathic pain by blocking cytokine activation, researchers say more studies are needed to determine how immune activation produces pain in the human body, as well as how it can be controlled.