Over the next several decades, a rapid increase in aging populations will challenge healthcare systems around the world. This is particularly true for efforts to treat pain, since the prevalence of pain increases with age, with accompanying decreases in physical function.
New research led by David Seminowicz and Jin Ro from the University of Maryland, Baltimore, US, now reveals how age as well as sex affect the strength of what’s known as endogenous pain modulation – in this case, how well the brain can dampen down pain – in a study of healthy rats.
The investigators found that both elderly male and elderly female animals lost their ability to endogenously inhibit pain. But each sex displayed distinct brain functional connectivity underlying this phenomenon, according to functional magnetic resonance imaging (fMRI), a brain imaging technique. Functional connectivity refers to the strength of connections between different parts of the brain.
Meanwhile, young males showed the strongest endogenous pain inhibition, while young females were less efficient at dampening pain. Here, too, distinct functional connectivity between different brain regions correlated with the sex differences.
“This study identifies how age and sex are key factors in pain modulation and brain networks in rodents. This is important groundwork for understanding how these factors relate to chronic pain variability in humans,” said Katherine Martucci, a pain researcher at Duke University, Durham, US, who was not part of the current study.
The new research appears in the June 2020 issue of the journal PAIN.
Putting endogenous pain modulation to the test
Ro said that a lack of knowledge about pain in elderly populations spurred the new work.
“As a demographic, older adults are really vulnerable to chronic pain conditions, but this is an understudied area. Our goal was to strengthen this field and do more pre-clinical studies to understand the mechanisms underlying age-related increases in pain conditions,” Ro said, referring to research in animals that could help to identify what’s going on in the nervous system during the pain that accompanies aging.
The new research built on the investigators’ previous work showing that endogenous pain modulation in rats depended on sex and was linked to the amount of testosterone, a sex hormone.
“Then we got interested in aging, because we know that testosterone levels decline with age, both in male and female populations. We wanted to link this idea with age-related changes in endogenous pain modulation,” said Ro.
The group began by looking at how age and sex affect endogenous pain modulation by using an experimental method known as diffuse noxious inhibitory control (DNIC). The idea behind DNIC is that “pain inhibits pain” – that is, that the response to something that causes pain can be lessened by applying another painful stimulus.
In this instance, to produce this pain inhibits pain effect in rats, first author Joyce Da Silva and colleagues injected capsaicin into the forepaw of rats; capsaicin is the active component of chili peppers that makes them “hot.” The researchers then tested how the animals behaved when heat was applied to the hind paw of the animals.
The investigators compared four different groups of healthy rats – young males, young females, old males, and old females – to see how DNIC differed according to age and sex.
As expected, the investigators saw a strong DNIC effect in young male and young female rats, as the animals took longer to withdraw the hind paw in response to the heat after having received the capsaicin. In other words, the rats could now withstand the heat longer.
But this effect lasted longer in male rats, which was consistent with what the researchers found in their earlier studies. And, in old male and old female rats, DNIC was conspicuously impaired. This suggested that the ability to dampen pain is not as strong in older animals.
“We knew already that chronic pain conditions compromise endogenous pain modulation efficiency in animals, but we now know that aging itself also does the same thing,” Ro said.
What’s taking place in the brain?
The researchers next performed fMRI experiments in each of the four groups of rats. They wanted to understand whether connections of the anterior cingulate cortex (ACC), an area known to be involved in endogenous pain modulation, with other areas of the brain could explain their findings. (The group performed the experiments in anesthetized rats 30 minutes after the animals had received the capsaicin, since that is the time when the pain inhibits pain effect was strongest in young male and young female rats).
Overall, the analysis found widespread differences in ACC functional connectivity with different brain regions, when comparing young males, young females, old males and old females. These findings suggested that the brain engages different strategies to modulate pain, depending on sex and age.
To dig deeper, Da Silva was keen to look at these group differences in the connectivity of the ACC with specific brain regions involved in endogenous pain modulation. That included a brain structure called the periaqueductal gray (PAG).
She found that young male rats showing a strong pain inhibits pain effect had particularly strong connectivity between the ACC and the PAG. There were more brain areas involved, but Da Silva highlighted the ACC-PAG connection as a signature response in young males that correlated with strong DNIC in this group.
“The ACC is known to facilitate and inhibit pain, but we think that in young males it is acting as an inhibitory control via connections with the PAG,” Da Silva said.
The picture was different in old males, however, where the pain inhibits pain effect was impaired. In this case, while the PAG showed increased connectivity with many brain regions, the ACC was not one of them.
“We think that maybe the missing ACC-PAG role underlies the impaired DNIC seen in older males,” Da Silva said.
Another important finding was the scale of connectivity of different brain regions with the ACC in each group. Young females, for example, showed more widespread brain connectivity with various areas in the cortex and the midbrain (part of the brainstem) than young males did. According to Da Silva, this indicates that several diffuse brain networks, not just ACC-PAG connectivity, are involved in DNIC in young females.
In old females, there was strong connectivity between the ACC and many areas, including the limbic system, a region known to be involved in the emotional response to pain. Da Silva speculated that these connections between the ACC and the limbic system may drive the emotional components of pain, which are common in elderly people.
“It is known from human studies that elderly patients with chronic pain develop a lot of emotional comorbidities such as depression, so we think that age-related impairments in ACC circuitries may be driving these comorbid conditions of chronic pain,” Da Silva said. Co-morbidity refers to the co-occurrence of two or more different conditions.
A more complicated picture in people
Overall, the findings show that there are two divergent ways in males and females that explain why old animals are less efficient at dampening pain: less connectivity between the ACC and PAG in old males, and strengthened connectivity between the ACC and the limbic system in old females.
“It looks like older brains are changing over time in a maladaptive way and require more areas to be engaged for pain modulation. Because DNIC is not working well at older ages, we think that the brain is trying to involve more regions to try and re-engage a level of pain inhibition, but it’s not really working,” Da Silva said.
Martucci said that animal studies like the current one are important for the pain research community, as they identify important general factors that alter pain processing, which can be looked at in more detail in human studies. But she stressed the important caveat that the situation is likely to be much more complex in people than in rodents.
“The effect of aging on pain processing is particularly complicated to understand. What is someone’s brain age versus their actual age? Aging effects on pain circuits might relate to individual differences in life events such as traumatic events or stress, and of course gender and sex play a role in this, too,” Martucci said.
And, Martucci added, “these experiments were done on cleanly bred rodents with few individual differences, so we would expect to see different results if tested in an inherently more variable human population. Doing a parallel human study is what we really want to see to confirm the results here,” Martucci added.
As for future studies, the research team wants to see whether boosting the connectivity between the ACC and PAG in aged animals can strengthen the pain inhibits pain effect and improve pain outcomes.
Further, Ro said, “there are perhaps non-pharmacological ways to enhance DNIC circuitry, such as exercise, which has been shown to improve osteoarthritis outcomes in elderly patients. The question is, if you combined exercise with experimentally strengthening DNIC pathways, would it further improve chronic pain outcomes?”
This story first appeared on the IASP Pain Research Forum and has been edited for RELIEF.
Fred Schwaller, PhD, is a postdoctoral researcher at the Max Delbrück Center for Molecular Medicine in Berlin, Germany.