For all they do protecting the body, immune cells can sometimes do more harm than good by setting off problems such as arthritis and allergies. Now, a study published in Science on May 26 uncovers a new mechanism through which immune cells known as microglia heighten sensitivity to pain: by breaking down the outer covering of neurons in the spinal cord that are involved in processing pain information. This action results in the brain interpreting the signals from those nerves as chronic pain. 

In the study, researchers based at McGill University in Canada mimicked nerve injury in 8 to 12-week-old mice and then collected what are known as projection neurons, which transmit signals to distant places in the central nervous system, from a region in the spine that processes pain signals. Using a stain that indicates the presence of a type of outer covering known as perineuronal nets (PNNs) on the projection neurons, the team found that the volume of these coatings fell by 76.3 percent over the three days after the injury was inflicted, and deposits of the stain turned up inside specialized immune cells called microglia. 

To determine how microglia reduced PNNs after nerve injury, the researchers divided a new cohort of mice into two groups. They deleted microglia from one group, and found that these mice did not exhibit hypersensitivity following mechanical injury, while control animals did. PNNs allow very specific modulation of the output of pain signals in the spinal cord, and when microglia break down the PNNs, this boosts projection neuron activity. 

See “Perineuronal Nets: A Mechanism to Control Brain Plasticity

The researchers also investigated whether the removal of the PNNs around the projection neurons induces pain. They erased a core protein in the PNN known as aggrecan by injecting the mice with the virus rAAV, which deleted a gene encoding for  the aggrecan. For comparison, they also injected another projection neuron of the same mice with AAV-Cre and a Cre-dependent adeno-associated virus expressing Chondroitinase ABC,  which degrades the sugar side chain glycosaminoglycan that binds PNNs. Following the removal of the sugar chain and the protein aggrecan from the mice's projection neurons, the mice experienced hypersensitivity to heat and also spontaneous pain as assessed via their facial expressions

The study’s authors conclude that microglia activated by injury degrade PNNs, which is then associated with pain sensitivity. Coauthor Arkady Khoutorsky, a neuroscientist at McGill, tells The Scientist that “we identified a new mechanism of chronic pain.” Specifically, he explains that the study identifies a mechanism that leads to neuropathic pain—a type of chronic pain caused by progressive nerve diseases. “We found that the activity of projection neurons can be directly enhanced in neuropathic pain,” Khoutorsky adds. 

Previous studies have shown that the activation of microglial cells after nerve injuries contributed to the development of neuropathic pain, but the mechanism for this was unclear. Richard Miller of Northwestern University, who has studied the mechanisms of pain in osteoarthritis but was not part of the new study, says that its findings are “creative and unexpected” and that it challenges a previous perception of perineuronal nets as mere structural supports.

Miller holds that PNNs and other types of extracellular matrices are complicit in many pain-related ailments, including those that originate outside the central nervous system.  “There are indications in medicine that when things go wrong in the extracellular matrix it can lead to pain,” says Miller. “This is all over the body and not just in the spinal cord.” For instance, Ehlers-Danlos syndrome, which involves pain in the skin, joints, and blood vessel walls, is known to be caused by the deficiency of an extracellular matrix protein.

In addition to how the lack of PNNs leads to nerve cell overactivity, Miller suggests it’s possible that a product of the matrix breakdown may be mediating pain by directly acting on the nerve cells. 

Miller notes that more research will be needed to find out whether the study’s findings apply to humans. 

“Neuropathic pain is the most difficult type of pain to treat mostly because we don’t understand how nerve injuries cause chronic pain,” says Khoutorsky. “We hope that by targeting this newly identified mechanism, future therapeutics could be developed to reverse neuropathic pain in patients.”