Activation of microglial GPR109A alleviates thermal hyperalgesia in female lupus mice by suppressing IL‐18 and glutamatergic synaptic activity

• Published in: Glia Vol. 70; no. 4; pp. 634 - 649
• Main Authors: Viatchenko‐Karpinski, Viacheslav, Kong, Lingwei, Weng, Han‐Rong
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.04.2022; Wiley Subscription Services, Inc
• Subjects: Analgesics; Animal models; Animals; Astrocytes; Attenuation; Chronic conditions; Chronic pain; Dorsal horn; EPSC; Female; glial neuronal interaction; Glutamatergic transmission; HCAR2; Hyperalgesia; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Hyperalgesia - metabolism; Inflammation; Interleukin-18 - metabolism; Interleukins; Lupus; Lupus Erythematosus, Systemic - complications; Lupus Erythematosus, Systemic - metabolism; MAP kinase; Mice; Mice, Inbred MRL lpr; Microglia; Microglia - metabolism; neuroinflammation; nociception; Pain; Pain perception; Receptors, G-Protein-Coupled; synaptic; Systemic lupus erythematosus; Thermal stimuli; HCAR2; nociception; glial neuronal interaction; EPSC; neuroinflammation; synaptic
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.24130

Many patients with systemic lupus erythematosus (SLE) live with chronic pain despite advances in medical management in reducing mortality related to SLE. Few animal studies have addressed mechanisms and treatment for chronic pain caused by SLE. In this study, we provide the first evidence for the analgesic effects of a GPR109A specific agonist (MK1903) and its action mechanisms in thermal hyperalgesia in female MRL/lpr mice, an SLE mouse model. Specifically, we show that MRL/lpr mice had a higher sensitivity to thermal stimuli at age 11–16 weeks, which was accompanied with significantly microglial and astrocytic activation, increases in p38 MAPK and glutamatergic synaptic activities in the spinal dorsal horn. We demonstrate that thermal hyperalgesia in MRL/lpr mice was significantly attenuated by intrathecal injection of MK1903. GPR109A was expressed in spinal microglia but not astrocytes or neurons. Its expression was significantly increased in MRL/lpr mice with thermal hyperalgesia. Activation of GPR109A receptors in microglia attenuated glutamatergic synaptic activity via suppressing production of interleukin‐18 (IL‐18). We provide evidence that activation of GPR109A attenuated thermal hyperalgesia in the SLE animal model via suppressing p38 MAPK activity and production of IL‐18. Our study suggests that targeting the microglial GPR109A is a potent approach for reversing spinal neuroinflammation, abnormal excitatory synaptic activity, and management of thermal hyperalgesia caused by SLE. Main Points In this study, we found that activation of spinal microglial GPR109A alleviates chronic pain in a female mouse model of systemic lupus erythematosus by suppressing IL‐18 production and glutamatergic synaptic activity.