Lysophosphatidic acid drives to mirror-image pain via corpus callosum-mediated propagation of inflammatory responses.

Pain transmission is considered a unilateral process; however, development of bilateral hyperalgesia, including mirror-image pain (MIP), challenges this notion. The neural basis underlying bilateral hyperalgesia remains unclear. We investigated whether microglial activation within the corpus callosum is associated with interhemispheric propagation of inflammatory responses contributing to MIP. In a photothrombotic reperfusion mouse model, lysophosphatidic acid (LPA) signalling was associated with microglial activation in the contralateral corpus callosum and MIP development. Furthermore, PF8380 or minocycline suppressed bilateral hyperalgesia with MIP, supporting the therapeutic relevance of targeting LPA signalling and microglial activation. Together, these data support a model of an inflammatory circuit involving ischemic-core LPA, callosal microglia, contralateral insular PGE₂ signalling, and contralateral ACC activation that contribute to MIP. Because dysregulated LPA signalling and microglial activation are features of other neuroinflammatory conditions, transcallosal glial crosstalk may also contribute to widespread pain syndromes. Our findings highlight the therapeutic potential of targeting LPA-related pathways.