Study sheds light on the role of immune cells and X-linked receptors in chronic pain resolution

A recent study conducted by a research team at the University of Alberta has shed light on disparities in the development and resolution of chronic pain between male and female mice. These findings have the potential to pave the way for targeted treatments for humans dealing with chronic pain in the future.

The study, which focused on mice experiencing chronic pain due to inflammation rather than direct injury, revealed that female mice exhibited greater sensitivity to the effects of immune cells called macrophages. Additionally, the research identified a receptor linked to the X chromosome that plays a crucial role in resolving both acute and chronic inflammation in both sexes.

Bradley Kerr

Bradley Kerr

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Principal investigator Bradley Kerr, who serves as a professor of anesthesiology and pain medicine in the Faculty of Medicine & Dentistry at the University of Alberta, explained the significance of their findings. “We’re always interested in understanding the triggers for pain, but in this study, we went up the next step to ask how pain resolves to determine how these immune cells are involved,” he said. Kerr, who is also an adjunct professor with the departments of pharmacology and physiology, highlighted the potential impact of immune cell composition on the development of chronic pain.

Chronic pain, defined as persistent pain lasting three months or longer beyond the typical healing period, affects approximately 20 percent of Canadians, with a higher prevalence among women than men, according to Pain Canada. Autoimmune conditions like multiple sclerosis, which can lead to chronic pain, also disproportionately impact women.

Kerr noted that it has only been in the past decade that scientists have consistently incorporated both male and female mouse models in their pain studies to investigate potential sex differences.

Kerr’s lab focuses on unravelling the causes of chronic pain in hopes of developing effective treatments. He emphasized the importance of understanding pain that no longer serves a protective purpose, such as the initial discomfort following an injury. “Having an understanding of where this pain is coming from and how it goes away naturally is really important, and I think we’re a step closer,” Kerr explained.

The researchers analyzed the pain pathways in their mouse models using various methods. Previous work in Kerr’s lab had shown that female mice had two to three times more of the pain receptor Tlr7 than males. In the current study, they genetically removed Tlr7 and observed that pain did not resolve properly.

In contrast, when mice with chronic pain were treated with an antiviral medication known to stimulate Tlr7 artificially, their pain resolved three to five days sooner than without treatment. Tlr7 is a receptor within the immune system that triggers an antiviral response when detecting a virus, leading to symptoms like fever-induced aches and pains.

Kerr expressed hope that their findings would inform future therapies and lead to the identification of potential treatments targeting the Tlr7 receptor. “We’re hoping to inform future therapies and identify things like the Tlr7 receptor that could be potentially very beneficial down the line if we can refine how to activate it in a controlled way,” Kerr stated.

The research underscores the close relationship between chronic pain and the functioning or malfunctioning of the immune system. Future treatments may need to be tailored to specific sexes. “We learned that you’ve got to stimulate the immune system in just the right way to get that proper resolution of pain,” Kerr explained. “If the macrophages don’t get activated or the pathways don’t get engaged properly at the start, that sets up this kind of continuous chronic pain state that doesn’t resolve.”

Kerr and his team plan to extend their research by investigating the effects of stimulating macrophages and Tlr7 on models experiencing pain caused by nerve injuries, moving beyond their focus on diseases like multiple sclerosis.

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