LPA4 in the spinal dorsal horn is a potential therapeutic target for inflammatory pain and neuropathic mechanical hypersensitivity.

Neuropathic pain is a major cause of chronic pain, but effective treatments remain limited. To investigate the role of lysophosphatidic acid receptor 4 (LPA4) in pain processing, we generated LPA4-knockout rats and evaluated inflammatory and multiple neuropathic pain models. LPA4 deficiency attenuated second-phase formalin responses and reduced mechanical hypersensitivity in the spared nerve injury and lumbar spinal stenosis models, without affecting baseline locomotor activity or mechanical sensitivity. RNAscope revealed Lpar4 expression in the spinal dorsal horn, mainly in astrocytes. Consistent with this distribution, spared nerve injury-induced astrocyte and microglial activation in the dorsal horn was suppressed in LPA4-knockout rats. Bulk RNA sequencing identified interleukin 1β as a candidate downstream mediator, and LPA-induced Il1b mRNA upregulation was not observed in LPA4-knockout astrocytes. These findings suggest that spinal LPA4 may contribute to inflammatory pain and neuropathic mechanical hypersensitivity, potentially through glial activation and interleukin 1β-related mechanisms in the spinal dorsal horn.