Role of Adenosine Kinase in Sphingosine-1-Phosphate Receptor 1-Induced Mechano-Hypersensitivities.

Autor: Lauro F; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA.; Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA., Giancotti LA; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA.; Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA., Kolar G; Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA.; Department of Pathology, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA., Harada CM; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA.; Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA., Harmon TA; Department of Chemistry, University of Florida, Gainesville, FL, 32610, USA., Garrett TJ; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA., Salvemini D; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA. daniela.salvemini@health.slu.edu.; Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO, 63104, USA. daniela.salvemini@health.slu.edu.
Jazyk: angličtina
Zdroj: Cellular and molecular neurobiology [Cell Mol Neurobiol] 2022 Nov; Vol. 42 (8), pp. 2909-2918. Date of Electronic Publication: 2021 Nov 13.
DOI: 10.1007/s10571-021-01162-8
Abstrakt: Emerging evidence implicates the sphingosine-1-phosphate receptor subtype 1 (S1PR1) in the development of neuropathic pain. Continued investigation of the signaling pathways downstream of S1PR1 are needed to support development of S1PR1 antagonists. In rodents, intrathecal (i.th.) injection of SEW2871, a selective S1PR1 agonist, activates the nod-like receptor family, pyrin domain containing 3 inflammasome, increases interleukin-1β (IL-1β) and causes behavioral hypersensitivity. I.th. injection of a IL-1β receptor antagonist blocks SEW2871-induced hypersensitivity, suggesting that IL-1β contributes to S1PR1's actions. Interestingly, previous studies have suggested that IL-1β increases the expression/activity of adenosine kinase (ADK), a key regulator of adenosine signaling at its receptors (ARs). Increased ADK expression reduces adenosine signaling whereas inhibiting ADK restores the action of adenosine. Here, we show that SEW287-induced behavioral hypersensitivity is associated with increased expression of ADK in astrocytes of the dorsal horn of the spinal cord. Moreover, the ADK inhibitor, ABT702, blocks SEW2871-induced hypersensitivity. These findings link ADK activation to S1PR1. If SEW2871-induced pain is mediated by IL-1β, which in turn activates ADK and leads to mechano-allodynia, then blocking ADK should attenuate IL-1β effects. In support of this idea, recombinant rat (rrIL-1β)-induced allodynia was blocked by at least 90% with ABT702, functionally linking ADK to IL-1β. Moreover, the selective A 3 AR antagonist, MRS1523, prevents the ability of ABT702 to block SEW2871 and IL-1β-induced allodynia, implicating A 3 AR signaling in the beneficial effects exerted by ABT702. Our findings provide novel mechanistic insight into how S1PR1 signaling in the spinal cord produces hypersensitivity through IL1-β and ADK activation.
(© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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