Lysophosphatidic acid and its receptor LPA 1 mediate carrageenan induced inflammatory pain in mice.

Lysophosphatidic acid receptor 1 (LPA ₁ ) is one of six G protein-coupled receptors (GPCRs) activated by the bioactive lipid, lysophosphatidic acid (LPA). Previous studies have shown that LPA ₁ signaling plays a major role in the pathophysiology of neuropathic pain. It has also been shown that the inhibition of phospholipase A ₂ , an enzyme upstream of LPA synthesis, reduces mechanical allodynia in experimental inflammatory orofacial pain. This suggests that the LPA-LPA ₁ axis may mediate inflammatory pain in addition to its known role in neuropathic pain, but this activity has not been reported. LPA ₁ 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 LPA ₁ knockout mice relative to wild-type littermate controls. A similar significant attenuation in allodynia was observed when mice were treated with an LPA ₁ 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 LPA ₁ signaling in the central nervous system (CNS) plays a key role in mediating orofacial inflammatory pain, identifying LPA ₁ as a potential therapeutic target for treating inflammatory pain with a brain-penetrant drug.
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