Involvement of lysophosphatidic acid (LPA) in tPA–induced central post stroke pain (CPSP) in mice

Abstract

This article introduces the recent publication (doi.org/ 10 . 1016 /j.ynpai. 2018 . 07 . 001 ) on the development of new animal model for central post stroke pain ( CPSP ) and its mechanisms through lysophosphatidic acid (LPA) signaling in mice. In this model, the photochemically induced thrombosis (PIT) at middle cerebral artery (MCA) of mouse was made by use of Rose Bengal ( 30 mg/kg, i.v.) and irradiation by green light ( 5 , 000 Lx) for 10 min through the dura mater. Bilateral hyperalgesia in the PIT model was observed when electrical stimulation–induced paw withdrawal (EPW) test using 250 (A δ ) and 2000 Hz (A β ) stimulation was used. As no significant thermal or mecha nical hyperalgesia was observed, we combined the treatment with tissue plasminogen activator (tPA), which was treated at 10 mg/kg (i.v.) 6 h after the start of PIT. Mice treated with tPA and PIT survived and showed stable bilateral hyperalgesia in electrical (EPW), thermal and mechanical nociception tests at least for 18 days without signifi cant behavioral abnormality to make the pain assessment difficult. The hyperalgesia in these tests were completely abolished in mice deficient of LPA 1 and LPA 3 . The systemic treatments of LPA 1 / 3 –receptor antagonist, Ki 16425 at 30 mg/kg (i.p.) twice daily for a week largely abolished the established and bilateral thermal and mecha nical hyperalgesia. Liquid Chromatograph–tandem Mass Spectrometer (LC– MS ⁄ MS) analysis revealed the PIT–induced and tPA–enhanced production of LPA in somato sensory cortex (S–I/II), but not in striatum or ventroposterial thalamus. Interestingly, significant production of LPA in mediodorsal thalamus (MD) was observed by tPA–combined PIT. It remains whether the LPA production in MD is related to the bilateral hyperalgesia in terms of emotional pain pathway. Further analyses of LPA measurements in various brain regions including insular cortex, which has right and left commissure, are highly required.