Lysophosphatidic acid receptor _1/3 antagonist inhibits the activation of satellite glial cells and reduces acute nociceptive responses

Abstract

Lysophosphatidic acid (LPA) exerts various biological activities through six characterized G protein‐coupled receptors (LPA1‐6). While LPA–LPA1 signaling contributes toward the demyelination and retraction of C‐fiber and induces neuropathic pain, the effects of LPA–LPA1 signaling on acute nociceptive pain is uncertain. This study investigated the role of LPA–LPA1 signaling in acute nociceptive pain using the formalin test. The pharmacological inhibition of the LPA–LPA1 axis significantly attenuated formalin‐induced nociceptive behavior. The LPA1 mRNA was expressed in satellite glial cells (SGCs) in dorsal root ganglion (DRG) and was particularly abundant in SGCs surrounding large DRG neurons, which express neurofilament 200. Treatment with LPA1/3 receptor (LPA1/3) antagonist inhibited the upregulation of glial markers and inflammatory cytokines in DRG following formalin injection. The LPA1/3 antagonist also attenuated phosphorylation of extracellular signal‐regulated kinase, especially in SGCs and cyclic AMP response element‐binding protein in the dorsal horn following formalin injection. LPA amounts after formalin injection to the footpad were quantified by liquid chromatography/tandem mass spectrometry, and LPA levels were found to be increased in the innervated DRGs. Our results indicate that LPA produced in the innervated DRGs promotes the activation of SGCs through LPA1, increases the sensitivity of primary neurons, and modulates pain behavior. These results facilitate our understanding of the pathology of acute nociceptive pain and demonstrate the possibility of the LPA1 on SGCs as a novel target for acute pain control.

The Role of Lysophosphatidic Acid in Neuropsychiatric and Neurodegenerative Disorders

“…Among LPAR1 agonists, it is worth mentioning UCM-05194, a non-lipid LPA agonist that was proven to exert therapeutical effects in disorders like AD, MS, neuropathic pain, and dementia [147]. LPAR1 antagonists such as Ki16425, Ki16198, and other thiazole derivatives [148,149], which also affect LPAR2 and LPAR3 to a lesser extent, are mainly studied for cancer and pulmonary fibrosis treatment; however, there is evidence pointing out their potentially beneficial effect in nociception [150]. Moreover, the LPAR1 antagonist AM095 was shown to inhibit microglial activation and attenuate neurological deficits after ischemic brain damage [151].…”

Lysophosphatidic acid receptor type‐1 mediates brain activation in micro‐positron emission tomography analysis in a fibromyalgia‐like mouse model

“…In these studies, the basal threshold in mechanical, thermal and electrical stimulation‐induced rapid pain responses was not affected in LPAR1‐KO mice. In contrast, LPAR1‐KO mice or systemic administration of LPAR1/3 antagonist showed a significant but partial blockade in the inflammatory pain induced by intra‐plantar application of carrageenan, complete Freund's adjuvant, or formalin (Hoshino et al, 2022; Srikanth et al, 2018; Ueda, 2019). Because we needed to use a relatively long‐lasting nociceptive stimulation by formalin to measure 18 F‐FDG uptake into activated brain regions, it would be very complicated to discuss the LPAR1‐mediated enhancement of formalin‐induced pain responses in the presence of ICS.…”