Millions of people worldwide use acupuncture to ease a variety of painful conditions, but it’s still not clear how the ancient treatment works. Now a new study of mice shows that insertion of an acupuncture needle activates nearby pain-suppressing receptors. What’s more, a compound that boosts the response of those receptors increases pain relief—a finding that could one day lead to drugs that enhance the effectiveness of acupuncture in people.
Researchers have developed two hypotheses for how acupuncture relieves pain. One holds that the needle stimulates pain-sensing nerves, which trigger the brain to release opiumlike compounds called endorphins that circulate in the body. The other holds that acupuncture works through a placebo effect, in which the patient's thinking releases endorphins. Neuroscientist Maiken Nedergaard of the University of Rochester Medical Center in New York state was skeptical about both hypotheses because acupuncture doesn’t hurt and often works only when needles are inserted near the sore site. Nedergaard instead suspected that when acupuncturists insert and rotate needles, they cause minor damage to the tissue, which releases a compound called adenosine that acts as a local pain reliever.
Nedergaard first assigned the study as a summer project to her then-16-year-old daughter, Nanna Goldman. Goldman and other researchers in Nedergaard’s lab lightly anesthetized mice to get them to hold still, inserted a needle into an acupuncture point on the lower leg, and sampled the fluid around the needle. They found a 24-fold rise in adenosine, which seemed promising.
Next, they tested whether boosting the action of adenosine helped alleviate two types of chronic foot pain—pain from inflammation, which underlies conditions such as arthritis; and pain from nerve damage, which occurs in conditions such as spinal cord injuries or complications of diabetes. By performing neurosurgery or by injecting a substance that promoted inflammation, the team created mice that had one of these conditions in their feet. Both types of chronic pain make mice recoil from mild stimuli that wouldn’t bother comfortable animals. Then the researchers tested each mouse’s sensitivity to two types of stimuli: touch, which they measured by how quickly the mouse pulled its sore foot off a metal filament; and heat, which they measured by shining a classroom laser pointer on the animal’s sore foot and measuring how quickly it pulled that foot away.
Inserting an acupuncture needle or locally injecting a drug that boosted adenosine’s action made the mice far less sensitive to pain. But neither treatment eased pain in mice that lacked a cell-surface receptor through which adenosine exerts its effects. These results demonstrate that adenosine acts as a biochemical messenger that helped soothe pain during acupuncture, says Nedergaard. The researchers obtained further confirmation by showing that both treatments lowered the activity in a pain-sensing area of the brain known as the anterior cingulate cortex.
To determine whether they could boost the pain-relieving effects of acupuncture, the researchers gave the injured mice a drug that leads tissue to accumulate more adenosine. The drug made adenosine stick around three times longer—and it tripled the period of pain relief from 1 hour to 3, the researchers report  online today in Nature Neuroscience. Although the drug they used, an anticancer drug called deoxycoformycin, is too toxic to use routinely in the clinic, Nedergaard calls the finding a “proof of principle that you can improve the effect of acupuncture.”
The work is “a landmark study” that was “very meticulously done, with a very clear hypothesis that was attacked on many different levels,” says Vitaly Napadow, a neuroscientist at Harvard Medical School in Charlestown, Massachusetts. More research is needed to test whether the pain-relieving pathway works not only in anesthetized mice but also in awake humans. “Whether this really flies in humans, I have no idea,” he says. “But I think it is a very important first step.”