ABOVE: Two images of the same dorsal root ganglion under different activation conditions in a live mouse are superimposed. Green fluorescent neurons respond to pinching the hind paw, and red fluorescent neurons fire together independent of peripheral stimuli. Qin Zheng

Spontaneous pain arises suddenly, without a clear trigger, and can feel like shooting, stabbing, burning, or electric shocks. It’s a common issue for people who have chronic pain and, because it lacks an external stimulus, difficult to treat. In a study published November 8 in Neuronresearchers link spontaneous pain in mice to coordinated firing of nonadjacent neurons in the dorsal root ganglia (DRG), which are collections of sensory neuron cell bodies just outside the spinal cord. The study authors report that this so-called cluster firing is driven by abnormal sprouting of sympathetic nerves into the DRG, which happens after injury.

“These paroxysms of spontaneous pain can really be debilitating. Because they’re totally unpredictable, there’s nothing a person can do to avoid them, so they cause enormous suffering and anxiety,” says Edgar Walters, who studies chronic pain at the University of Texas Health Science Center at Houston and did not participate in the work. “The work addresses a very important clinical problem,” he adds, and “is quite a beautiful explanation for how, after peripheral nerve injury, you get one kind of spontaneous pain.”

“The most interesting thing about this paper is that—rather than looking at individual neurons and how they may or may not change after an injury—they actually look at a population level, so how the neurons work together in a group and how that might contribute to kind of pain that we have not really done a great job modeling,” says Erin Young, who studies pain at the University of Kansas Medical Center and also was not involved in the study.

In work published in 2016, neuroscientist Xinzhong Dong’s group at the Johns Hopkins University School of Medicine and their collaborators describe an imaging technique they developed to monitor more than 1,600 neurons in the DRG of live mice. In that study, they generated mice with a genetically encoded calcium sensor that fluoresces when the neurons are activated. They then tracked the response of sensory neurons to pain evoked by pinching a paw, injecting a drug that causes inflammation, or exposing the animals to heat. The researchers watched adjacent DRG neurons fire together in a process they called coupled activation.

While it was clear that the neurons fired together in response to painful stimuli, Dong says, his team wondered what would happen if they observed the DRG neurons without providing any sensory input. For the new paper, postdoc Qin Zheng imaged mice with the calcium sensor for up to two hours at a time and saw clusters of nonadjacent neurons firing together every 10 minutes or so in mice who’d had prior nerve injuries. Based on a literature search, it seemed as though the cluster firing they were seeing could be caused by sympathetic nerves improperly growing into the DRG, a phenomenon first reported in 1993.

These paroxysms of spontaneous pain can really be debilitating.

—Edgar Walters, University of Texas Health Science Center

Dong contacted Jun-Ming Zhang of the University of Cincinnati, an expert in this abnormal sympathetic nerve innervation. Together, Dong’s and Zhang’s teams showed that the cluster firing in neurons correlated with behavioral indicators of spontaneous pain, including paw licking, flinching, and jumping. And the site of the clusters wasn’t everywhere in the DRG, but specifically localized at sympathetic nerve entry points. The researchers determined that the sprouting sympathetic nerves release the neurotransmitter norepinephrine, which acts on receptors on the DRG sensory neurons, causing cluster firing and spontaneous pain. The researchers were able to relieve the pain by blocking sympathetic neuron activity, DRG neuron cluster firing, or the receptors on DRG neurons that respond to norepinephrine.

Tracking cluster firing allows researchers to objectively measure spontaneous pain and the contribution of sympathetic innervation. Before, we knew the innervation was happening, but we didn’t know what the consequence was, says Dong.

“The problem is still, how do you treat this kind of pain condition based on what we found,” Zhang says. People have tried treating pain by blocking sympathetic nerves in the past with mixed results, so there’s a lot that needs to be done to leverage the therapeutic potential of the findings.

“If you ask chronic pain patients what their symptoms are, spontaneous pain is almost always there [and] you can’t avoid it,” says Jeffrey Mogil, who studies pain at McGill University in Montreal and was not involved in the work. “If someone has a new mechanism that might underlie spontaneous pain, that strikes me, if true, as a big deal,” he adds. Because the behaviors that the authors measured in the mice only happen about eight times an hour, it would be nice to have the link to cluster firing “corroborated with another measure of spontaneous pain that wasn’t so rare,” such as grimacing, burrowing, ultrasonic vocalization, or conditioned place preference, he says. “It’s challenging to measure, but it should, in fact, be the number one priority” in pain research.

The sympathetic nervous system is responsible for the body’s fight or flight response and is thus activated during times of stress. Sympathetic innervation and sprouting could therefore be “a way by which psychological, physical, or emotional stress could physically induce pain in those who already have a chronic pain condition,” says Young. Every time we identify a possible explanation, “it starts to deconstruct the stigma that we have associated with some of these pain conditions where people feel like it can’t be that bad, or it doesn’t make any sense. Well, it does make sense. We just don’t know how yet.”