Lysophosphatidic acid and its receptor LPA₁ mediate carrageenan induced inflammatory pain in mice

Lysophosphatidic acid receptor 1 (LPA₁) is one of six G protein-coupled receptors (GPCRs) activated by the bioactive lipid, lysophosphatidic acid (LPA). Previous studies have shown that LPA₁ signaling plays a major role in the pathophysiology of neuropathic pain. It has also been shown that the inhibition of phospholipase A₂, an enzyme upstream of LPA synthesis, reduces mechanical allodynia in experimental inflammatory orofacial pain. This suggests that the LPA-LPA₁ axis may mediate inflammatory pain in addition to its known role in neuropathic pain, but this activity has not been reported. LPA₁ signaling was disrupted in mice with both genetic and pharmacological approaches. Mice were then evaluated for behavioral and molecular characteristics of allodynia in a model for inflammatory orofacial pain. Pain behavior was significantly attenuated in LPA₁ knockout mice relative to wild-type littermate controls. A similar significant attenuation in allodynia was observed when mice were treated with an LPA₁ antagonist, AM095, following validation of its potency and selectivity. This was accompanied by a marked reduction in phosphorylated cAMP response element-binding protein (pCREB) labelling in the cerebral cortex. Interestingly, the reduction in allodynia was observed with central, but not systemic drug administration. Taken together, our findings indicate that LPA₁ signaling in the central nervous system (CNS) plays a key role in mediating orofacial inflammatory pain, identifying LPA₁ as a potential therapeutic target for treating inflammatory pain with a brain-penetrant drug.