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Brain Networks Controlling Endogenous Pain Modulation Differ According to Age and Sex

fMRI study in healthy rats reveals differences in functional connectivity in young versus old, male versus female animals

by Fred Schwaller


24 April 2020


PRF News

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fMRI study in healthy rats reveals differences in functional connectivity in young versus old, male versus female animals

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, University of Maryland, Baltimore, US, now reveals how age as well as sex affect the strength of endogenous pain modulation, 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 circuitry underlying this phenomenon, according to functional magnetic resonance imaging (fMRI).

 

Meanwhile, young males showed the strongest endogenous pain modulation, while young females were less efficient at dampening down 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. Martucci does pain brain imaging work but was not part of the current study, which appeared online January 17, 2020, in 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 preclinical studies to understand the mechanisms underlying age-related increases in pain conditions,” Ro told PRF.

 

The study built on the investigators’ previous research showing that endogenous pain modulation in rats was sex dependent and linked to testosterone levels (Da Silva et al., 2018).

 

“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 age- and sex-related changes in endogenous pain modulation by using diffuse noxious inhibitory control (DNIC) as a method to induce endogenous pain inhibition. To produce this “pain inhibits pain” effect in rats, first author Joyce Da Silva and colleagues injected capsaicin into the forepaw of rats and then tested the behavioral response to heat stimulation of the hindpaw. 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 robust DNIC in young male and young female rats, as indicated by increased hindpaw withdrawal latencies to heat stimuli as early as 15 minutes after capsaicin injection. But DNIC lasted longer in male rats, which confirmed the investigator’s previous findings of sex differences in endogenous pain modulation. But in old male and old female rats, DNIC was conspicuously impaired, suggesting that endogenous pain modulatory control is compromised 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 told PRF.

 

Underlying differences in brain circuitry

The researchers next performed fMRI experiments in each of the four groups of rats to understand whether functional connectivity of the anterior cingulate cortex (ACC), an area known to be involved in endogenous pain modulation, could explain the age- and sex-related differences in DNIC. They performed the experiments in anesthetised rats 30 minutes after capsaicin injection into the forepaw, a time point when DNIC 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 pain modulatory strategies, 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, such as the periaqueductal gray (PAG).

 

She found that young male rats with strong DNIC had particularly strong connectivity between the ACC and the PAG. There were more areas involved, such as the hippocampus and the deep mesencephalic nucleus, but Da Silva highlighted the ACC-PAG connectivity 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 told PRF.

 

The picture was different in old males, however, where DNIC was impaired.

 

“Old males were interesting because we saw increased connectivity between the PAG and a lot of brain regions such as the raphe nuclei and the hippocampus, but not with the ACC. 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 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. Da Silva speculated that these connections between the ACC and the limbic system may drive the affective 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.

 

 

Boosting DNIC

Overall, the findings indicate that there are two divergent mechanisms in males and females that explain the impairments in endogenous pain inhibition seen in old animals: a reduction in ACC-PAG connectivity in old males, and strengthened ACC-limbic system connectivity 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 that 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 told PRF.

 

“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 research, the team wants to see whether boosting ACC-PAG connectivity in aged animals can strengthen DNIC 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?” Ro wondered.

 

Fred Schwaller, PhD, is a postdoctoral researcher at the Max Delbrück Center for Molecular Medicine in Berlin, Germany.

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