Highlights From the 10th Annual NIH Pain Consortium Symposium
No institute at the National Institutes of Health (NIH) is dedicated exclusively to pain research, so the multi-institute Pain Consortium was created in 1996 to coordinate research across the many laboratories conducting pain studies at the Institutes. This year, the Pain Consortium held its 10th Annual Symposium, “Looking Back and to the Future,” May 26-27 at the NIH in Bethesda, Maryland, US.
Among the highlights of the conference were presentations by the three finalists for the Mitchell Max Award, given in honor of the late Max, who dedicated his life to pain research at the NIH and the University of Pittsburgh, US. The award goes to the best poster presenter; the finalists also made short slide presentations of their work.
The impact of exercise on pain and stress
Mark Pitcher, a visiting postdoctoral fellow in the lab of Catherine Bushnell at the NIH’s National Center for Complementary and Integrative Health (NCCIH), took the prize with his findings, from a rat model of persistent inflammatory pain, that even minimal voluntary exercise has a beneficial effect on pain and stress.
The benefits of exercise are well established in rodents and humans for both physical and mental health, including for pain, but scientists are still working to understand the mechanisms involved (Kroll, 2015). “Many studies have used forced treadmill running to study effects of exercise on pain in rodents,” Pitcher said. Sometimes experimenters use electric shock to compel animals to run on a wheel, which increases anxiety, stress, and inflammation. But “rats, like humans, don’t like to be forced to do anything, much less run,” Pitcher said. Consequently, he and his colleagues wanted to test whether voluntary exercise alone would be sufficient for exercise-induced analgesia.
The investigators injected rats with complete Freund’s adjuvant (CFA) in the ankle joint, which produces persistent inflammation and pain; control rats received a sham injection. Rats were allowed access to a running wheel for two hours per day, four days per week, for three weeks following injection. Each week, the researchers measured rats’ ankle width and range of motion to track inflammation. “We found that exercise did not change the level of inflammation—the swelling was elevated and remained elevated,” said Pitcher.
The researchers next tested the animals’ pain hypersensitivity with a device that measures the amount of weight rats placed on their inflamed and contralateral, uninflamed ankles. “The amount of weight an animal is willing to put on its hindpaw is a good measure of pain—it’s the animal telling us what it is comfortable with,” Pitcher noted. Sedentary rats had a persistent deficit in weight bearing on the inflamed joint over the three-week study. “But the exercise group had the capacity to bear weight on the inflamed paw,” he said. “At week 3, they were able to support as much weight on that injured paw as they were at baseline.” In a test of thermal sensitivity, exercise also provided clear analgesic benefits, maintaining animals’ withdrawal thresholds near baseline.
Pitcher and colleagues also measured plasma corticosterone as an indicator of stress. After CFA injection, corticosterone levels in sedentary rats were roughly double those of sham rats, but “access to exercise prevented those increases and actually kept corticosterone levels comparable to sham animals,” Pitcher said.
One criticism of experiments that use wheel running in lab animals is that the behavior might simply be a compulsive reaction to life in captivity—a behavior that wild rodents would not exhibit. But Dutch scientists disproved that notion by setting up running wheels in the wild and recording videos of the animals that used them. Hundreds of mice elected to run on the wheels, as did other animals, even slugs (Meijer and Robbers, 2014). “Healthy rodents enjoy running,” Pitcher added.
Pitcher chose to study rats, which vary from one animal to another in their affinity for wheel running, rather than mice, which are notoriously enthusiastic runners. “Rats are sort of closer to humans in that way,” Pitcher told PRF. “We saw lazy rats and others that liked to run more.” Considering that variability among rats, Pitcher examined the relationship between analgesic benefit and how much running each rat did. “We thought the more animals ran, the better they would do in terms of pain and stress.” But surprisingly, the distance run had no correlation with weight bearing or corticosterone levels. Some rats that ran a lot saw only modest benefits, whereas others that ran only a little had great improvements, so there seemed to be no particular minimum requirement. “It’s not how much exercise you do, but having regular access to it that seems important,” Pitcher said. Regardless of the amount, “exercise is analgesic, and it reduces stress in this model of inflammatory pain,” he concluded.
Scanners, restraint, and stressed-out rats
Brain-imaging studies in rodents have provided a valuable corollary to those in humans, but getting animals into a functional magnetic resonance imaging scanner presents unique challenges. Another member of the Bushnell lab at NCCIH, Lucie Low, presented her work investigating those challenges. In order to perform brain imaging on rodents, researchers must first train the animals to withstand being restrained in, and the noise of, the scanner. “Both of these are pretty intense stressors. We want to understand what effect the training has on the animals in the first place,” said Low.
To train the rats, Low lightly anesthetized and then restrained the animals in an apparatus designed to mimic the imaging scanner, after which she subjected them to 90-decibel noise for 30 minutes. A control group of rats woke up unrestrained and were allowed to explore their pen, which contained the scanner-like apparatus—wiped clean to remove the smell of previously restrained animals—while exposed to 18-decibel noise for 30 minutes (a much less stressful experience). A second control group of rats was treated the same—unrestrained but still exposed to the apparatus and the lower-level noise—but experiments with those rats were performed on a separate day from the other two groups. Low then measured corticosterone levels to assess the stress levels of the animals. As predicted in the restrained group, “corticosterone levels were sky high compared to [those of] the rats in the second control group,” Low said. But, surprisingly, the non-restrained control animals that were exposed to the cleaned apparatus on the same day as the restrained rats also displayed elevated corticosterone levels, indicating they had somehow been stressed by the testing of the restrained animals.
Low hypothesizes that the restrained animals tested earlier in the day left behind some sort of olfactory stress cue that the control rats tested on the same day picked up on. The unrestrained rats tested on the same day also had lower withdrawal thresholds to a thermal stimulus than the rats tested on a different day. Low urged researchers to consider the effects of stress on rodent imaging experiments. “If you are getting this increase in stress hormones, the likelihood is that you are affecting brain processing of pain, because the two are so closely interlinked.”
Much-needed research on an overlooked issue
African Americans face tremendous, well-documented disparities in pain care: they are less likely to receive analgesic medications for pain, pharmacies in black neighborhoods are less likely to carry adequate supplies of prescription pain medications, and, in general, people with higher socioeconomic status are more likely to be treated with opiate medications in the hospital (see NIH infographic).
To better understand factors contributing to those disparities, Kate Yeager, a nurse researcher at Emory University, Atlanta, US, is studying the influence of individual, interpersonal, and neighborhood factors on around-the-clock opiate adherence in a socioeconomically diverse group of African Americans. “I decided to focus on African Americans because there is a lot of heterogeneity in the African American population, but it is rarely examined,” Yeager told PRF in an email. Yeager focused on patients being treated with opiates for cancer pain—a treatment most effective when taken every 12 hours around the clock.
To measure patient adherence, Yeager is using self-report forms and a device that fits atop patients’ pill bottles called the medication event monitoring system (MEMS) cap, which records data on when a pill bottle has been opened. “The caps give us lots of information,” Yeager said. After patients use the caps for a month, Yeager collects the caps and downloads the data stored within, which provides insights into how well patients adhered to their medication schedule. Yeager will also be conducting in-depth personal interviews with subjects to assess the factors affecting adherence.
Yeager currently has 64 patients from the Atlanta metropolitan area enrolled in the study and hopes to double that number in the coming months. Although her data are preliminary, she presented a glimpse of her findings so far. Subjects reported varied symptoms with an average pain intensity of 4.6 out of 10 on a brief pain inventory. According to patients’ self-reports about taking their medication over the prior four days, subjects adhered to their medication schedule about 54 percent of the time, which was confirmed by the MEMS cap data. Thirty-two percent of subjects reported never skipping a dose, but other subjects attributed skipped doses to falling asleep or not needing the pain medication. Yeager hopes that her work will lead to a better understanding of how healthcare providers can better address the disparities faced by African Americans living with pain.
“My next step will be to develop and test an intervention to increase pain relief to this group,” Yeager said. “Depending on the findings, that intervention might focus on the individuals with pain, their social support network, or their larger neighborhood and community.”
Note: PDFs of the presentations discussed above are available on the NIH web site: Mark Pitcher, Lucie Low, Kate Yeager. A webcast of the entire symposium is also available: Day 1 and Day 2.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.
Image credit: NIH
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