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.