Chronic pain affects millions of people worldwide, and finding effective ways to manage it remains a significant challenge. Approximately 40% of individuals struggle to find adequate relief from current treatments. To improve this, researchers are working to understand the processes that cause short-term pain to become long-lasting.
Recent research in animals has shed light on how certain immune cells, called monocytes, might contribute to chronic pain.
Previous studies in mice have shown that blood-borne monocytes infiltrate the spinal cord and act with local microglia to promote pain chronification after nerve injury. Moreover, monocytes and macrophages that express the CXCR1 receptor have been found to contribute to arthritis pain and chemotherapy-induced allodynia through interactions with nociceptive neurons in the dorsal root ganglia (DRG).
Previous studies in mice have suggested that monocytes from the blood can travel to the spinal cord. There, they act with other local immune cells (microglia) to increase the likelihood that pain becomes chronic after a nerve injury. Additionally, monocytes and macrophages (specifically those with a receptor called CXCR1) have been linked to arthritis pain and pain caused by chemotherapy. They do this by interacting with pain-sensing nerve cells in an area called the dorsal root ganglia (DRG).
A recent study looked closer at this process. Researchers investigated whether a specific enzyme inside cells, called N-acylethanolamine acid amidase (NAAA), plays a role in how long-term pain develops after an initial painful experience (a process known as “hyperalgesic priming”). Using a mouse model, this study suggests that circulating monocytes are involved in the progression to chronic pain and describes some of the ways this might happen.
Key Discoveries from the Study
The researchers conducted several experiments using mouse models of hyperalgesic priming. Here are some of their key findings:
- When NAAA was blocked or a related protein called Peroxisome proliferator-activated receptor alpha (PPAR-α) was activated during the early stages of hyperalgesic priming, it stopped the pain from becoming long-lasting. Removing NAAA entirely in the mice had a similar effect.
- Mice that specifically lacked NAAA in certain immune cells (including monocytes, macrophages, and neutrophils) were less likely to develop chronic pain. In contrast, mice with more NAAA or less PPAR-α in these same cells were more prone to it.
- Removing circulating monocytes made the mice resistant to developing long-lasting pain; however, removing other immune cells, such as neutrophils or certain macrophages in the paw, did not have the same effect.
- The early phase of hyperalgesic priming was associated with an increase in activated monocytes in the bloodstream.
From these findings, the researchers highlighted three important points:
- The signalling pathway involving NAAA and PPAR-α appears to control how monocytes are recruited.
- Activated monocytes seem to work together with the first pain-sensing nerve cells to kickstart the priming process.
- This process can be broken down into several distinct steps, each with its own mechanisms.
What Do These Findings Suggest?
While it’s likely that various factors contribute to how pain becomes chronic, the results of this study suggest there’s at least one crucial point that needs to be passed for lasting pain to develop.
The experiments also indicated that the protective effects of blocking NAAA depend on activating PPAR-α. These effects were observed only in one sex and were limited to a three-day window after an injury. The authors suggest that future human studies could explore whether these “pain-stopping” agents might offer a way to prevent long-term pain after physical trauma.
Disclaimer: This blog post is based on a research study conducted in mouse models. The findings may not directly translate to humans. More research is needed to understand the full implications for chronic pain in people.
