Chronic, aching pain after an injury or operation may be all in your head. Researchers now think they’ve figured out exactly how brain wiring goes haywire to cause persistent pain—and how to fix it.

In mice with peripheral nerve damage and chronic pain from a leg surgery, a broken circuit in a pain-processing region of mammalian brains caused hyperactive pain signals that persisted for more than a month. Specifically, the peripheral nerve damage seemed to deactivate a type of interconnected brain cells, called somatostatin (SOM) interneurons, which normally dampen pain signals. Without the restraints, neurons that fire off pain signals—cortical pyramidal neurons—went wild, researchers report in Nature Neuroscience.

But the circuitry could be repaired, the researchers found. Just by manually activating those pain-stifling SOM interneurons, the researchers could shut down the rodents’ chronic pain and keep the system working properly—preventing centralized, chronic pain from ever developing.

“Our findings suggest that manipulating interneuron activity after peripheral nerve injury could be an important avenue for the prevention of pyramidal neuron over-excitation and the transition from acute postoperative pain to chronic centralized pain,” the authors, led by neuroscientist Guang Yang at New York University School of Medicine, conclude. Yang and his colleagues envision future drugs or therapies, such as transcranial magnetic stimulation, to tweak the activity of the interneurons to prevent malfunctioning pain signaling.

The study is just in mice, so it needs repeating and verifying before the line of research can move forward. That said, the work is backed by and in-line with a series of human and animal studies on chronic pain.

Earlier research found that chronic pain is coupled with alterations and hyperactivity in a pain-processing region of mammalian brains called the primary somatosensory cortex, or S1. This region is a strip across the top of the brain that spans the left and right hemisphere—like a headband over the brain. Within S1, chronic pain is linked to structural and functional changes in those pain-signaling neurons—the cortical pyramidal neurons. These changes include rearranged ion channels and higher levels of excitation.

Around those pain-signaling neurons are several types of interneurons that precisely regulate and control pain signals. These include parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal polypeptide (VIP)-expressing interneurons.

Painful connections

To figure out how all those brain cells may be working together—or not working—to regulate pain, the researchers turned to a mouse model of chronic pain. In this model, researchers carefully operate on the rodents’ left thigh. They precisely damage peripheral nerves in the leg—the tibial and common peroneal nerves—while leaving the main sural nerve intact.

Then, the researchers used two-photon calcium imaging to check out the activity of neurons in awake mice placed in a head restraint. First off, the researchers noted hyperactivity in cortical pyramidal neurons in the S1 brain region of mice with chronic pain, compared with those in mice that underwent a sham operation. Yang and his team also found that SOM and PV interneurons had less activity. Specifically, the SOM cells of chronic pain mice were 52 percent less active than those of sham-operation mice a month after the surgeries. They also noted that VIP interneurons were more active than normal in the chronic pain mice.

Based on the data and findings from earlier studies, the researchers speculated that during chronic pain, VIP interneurons were shutting down pain-stifling SOM and PV interneurons, thus allowing pain signaling in the pyramidal neurons to go crazy. Put another way:

VIP↑ = SOM/PV↓ = pyramidal cells↑ = chronic pain

To test this hypothesis, the researchers purposefully infected the rodents’ SOM cells with a genetically engineered virus that allowed them to control the cells’ activity. With the SOM cells manually turned on in the mice modeling chronic pain, the hyperactivity of their pain-signaling neurons dropped, and the mice were in less pain, based on results from a paw-pressure pain test.

The researchers didn’t see the same effect when they activated PV interneurons, suggesting that these cells may not be strong enough to effectively dampen wild pain signaling.

Next, the researchers wanted to see if SOM activation could prevent chronic pain from even developing. Using the same method, the researchers turned on SOM cells of mice in the first week after their peripheral nerve-damaging surgery. They found that the SOM activation prevented the pyramidal neurons from ever becoming hyperactive.

“Our study provides, to our knowledge, the first direct evidence that impaired SOM cell activity is involved in the development of neuropathic pain,” the researchers conclude. They note that future studies should look at whether hyperactive pyramidal cells alone—with no operations—can cause pain in mice. Future studies should also look at whether manipulating other cells, such as VIP or other pain-signaling neurons, could play a role in chronic pain.

If the findings hold up, the researchers are optimistic that drugs or new therapies could specifically target SOM cells, which have distinct cellular features that interventions could home in on.

Nature Neuroscience, 2017. DOI: 10.1038/nn.4595 (About DOIs).