Researchers today may have shined further light on a curious quirk of certain antidepressants: their ability to not only help balance out a person’s mood but alleviate their chronic nerve pain as well.

The researchers were able to demonstrate that tricyclic (TCAs) antidepressants were more effective in mice that lacked the ability to produce a protein, RGS9-2, known to interact with the brain’s nucleus accumbens, a region important to regulating our reward system. Their findings, published today in the Proceedings of the Natural Academy of Sciences, indicate that TCAs, as well as Selective Serotonin-Norepinephrine inhibitors (SNRIs), work to relieve pain through this reward system, at least in part.

RGS9-2, whose production is controlled by the gene RGS9 in both mice and men, is already known to regulate the signaling potential of dopamine and opioid receptors in the nucleus accumbens. The more RGS9-2 present, the less effective these receptors become, and vice-versa. In lab experiments using mice that had their RGS9 gene disabled, opioid drugs such as morphine became ten times more potent than they usually would, as well as more addictive.

A similar effect was seen in the current study’s RGS9-deficient mice, also suffering from chronic neuropathic pain, when given a low dose of the TCA desipramine. Not only was the drug’s effectiveness increased but it also began to work quicker in the mice than it would otherwise. Previous studies have shown that these antidepressants help reduce chronic pain by interacting with the spinal cord, but this is the first study to show that they directly influence the brain as well.

"Our data reveals that antidepressants that target specific neurotransmitters in the brain, particularly TCAs and SNRIs, regulate chronic pain and depression-related symptoms through actions in the nucleus accumbens," said study senior author Dr. Venetia Zachariou, an Associate Professor in the Fishberg Department of Neuroscience and the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, in a statement. "We don't yet know if the typical pain-processing pathways in the spinal cord and the pathways we've identified in the brain reward center are directly linked, but we now know more about the cellular pathways that need to be activated in order to achieve pain relief and that effective therapeutics must target both pathways."

Neuropathic pain, a condition where some of a person’s nerves became permanently damaged or die off, and which is often caused by injury, infection, and as a side effect of chemotherapy, is difficult to manage for patients and their doctors alike. The variation and frequency of pain proves to be different for any two people suffering from it. While some have shooting back pain, others have a burning sensation running down their legs. And its chronic nature makes it hard for narcotic painkillers, which are habit-forming, to be used for extended periods of time. Antidepressants, on the other hand, present a non-addictive option, which has led to doctors prescribing them more often for chronic nerve pain as time has gone on.

In addition to better understanding how and why these antidepressants work to treat nerve pain, the authors’ latest findings may point to new areas of research to be explored in better treating the debilitating ailment.  

"We found that the molecular pathways required for recovery from neuropathic pain are controlled by RGS9-2," said lead author Vasiliki Mitsi, a PhD student in the Zachariou lab at the Icahn School of Medicine at Mount Sinai. "In addition, we discovered that by inhibiting RGS9-2, the function of hundreds of other molecules that are important for pain-relief and mood-elevation was boosted."

Of course, the body is nothing if not a complex machine. While RGS9-2 deficient mice are more sensitive to painkillers and antidepressants, other research has shown that they have decreased motor coordination and working memory.

So it appears that it will take time to find out if RGS9-2 inhibition can truly be a (safe) avenue of pain treatment in people.

Source: Vasiliki Mitsia V, Terzia D, Purushothaman I, et al. RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states. Proceedings of the Natural Academy of Sciences. 2015. OK