Kyoto, Japan -- A stroke is a devastating condition that disrupts proper brain function. After a stroke, many patients will typically experience pain in the limbs on the side of their bodies opposite to the brain lesion. In rare cases, pain also develops on the same side as the lesion, spreading bilaterally in a mirror-like manner. This is a phenomenon known as bilateral pain, or mirror-image pain.
The lipid Lysophosphatidic acid, or LPA, has attracted attention as a molecule that may exacerbate chronic pain. LPA is derived from cell membranes and other cellular components that regulate inflammation, vascular function, and cell migration, and its levels tend to increase following tissue injury.
A team of researchers previously reproduced mirror-image pain in a mouse model and established the involvement of LPA in strokes. However, the pathways through which pain and inflammation brain signals propagate to the contralateral side had remained unclear, prompting them to investigate further.
"The central question underlying our study is: why does pain occur after a stroke, and why does it sometimes spread to both sides of the body?" says first author Hiroyuki Neyama of Kyoto University.
Using imaging mass spectrometry, the researchers analyzed mouse brains after ischemia-reperfusion injury, enabling them to directly measure molecules within tissue sections and to visualize increases in LPA and other molecules, such as the pain-related mediator PGE2. They also used immunostaining to examine microglial activation, allowing them to correlate molecular distribution maps with cellular responses.
The team's analysis revealed a sequential pathological process that ultimately results in bilateral pain. First, unilateral brain injury after a stroke triggers an increase in LPA, followed by the activation of microglia, and then by the propagation of inflammation through the corpus callosum and elevation of PGE2, finally leading to mirror-image pain.
With these methods, the researchers were able to visualize the coordinated involvement of LPA, microglia, and PGE2 for the first time, highlighting the significance of these imaging methods for understanding the functions of bioactive molecules in relation to their spatial localization within tissues.
"What impressed us most was our ability to visualize previously unseen inflammatory processes in the brain as molecular images of LPA and PGE2," says corresponding author Yuki Sugiura.
These findings demonstrate the therapeutic potential of targeting LPA production and microglial activation to treat post-stroke pain. The team next plans to investigate whether the pathological process they discovered contributes to neuroinflammation and chronic pain beyond strokes.
