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

Abstract

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.