GPR183-Oxysterol Axis in Spinal Cord Contributes to Neuropathic Pain

Abstract

Neuropathic pain is a debilitating public health concern for which novel non-narcotic therapeutic targets are desperately needed. Using unbiased transcriptomic screening of the dorsal horn spinal cord after nerve injury we have identified that Gpr183 (Epstein-Barr virus-induced gene 2) is upregulated after chronic constriction injury (CCI) in rats. GPR183 is a chemotactic receptor known for its role in the maturation of B cells, and the endogenous ligand is the oxysterol 7a,25-dihydroxycholesterol (7a,25-OHC). The role of GPR183 in the central nervous system is not well characterized, and its role in pain is unknown. The profile of commercially available probes for GPR183 limits their use as pharmacological tools to dissect the roles of this receptor in pathophysiological settings. Using in silico modeling, we have screened a library of 5 million compounds to identify several novel small-molecule antagonists of GPR183 with nanomolar potency. These compounds are able to antagonize 7a,25-OHC-induced calcium mobilization in vitro with IC 50 values below 50 nM. In vivo intrathecal injections of these antagonists during peak pain after CCI surgery reversed allodynia in male and female mice. Acute intrathecal injection of the GPR183 ligand 7a,25-OHC in naïve mice induced dosedependent allodynia. Importantly, this effect was blocked using our novel GPR183 antagonists, suggesting spinal GPR183 activation as pronociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify this receptor as a potential target for therapeutic intervention. SIGNIFICANCE STATEMENTWe have identified several novel GPR183 antagonists with nanomolar potency. Using these antagonists, we have demonstrated that GPR183 signaling in the spinal cord is pronociceptive. These studies are the first to reveal a role for GPR183 in neuropathic pain and identify it as a potential target for therapeutic intervention.These studies were supported by the Saint Louis University start-up funds of Dr.

The oxysterol receptor GPR183 in inflammatory bowel diseases

“…A chemical inhibitor which prevents binding of 7α,25-diHC to GPR183 and hence 7α,25-diHC-dependent migration of immune cells can be used as a GPR183 blocker (Braden et al, 2020;Gessier et al, 2014). In mice, this inhibitor replicated DC positioning phenotypes of the Gpr183 knockout (Lu, Dang, McDonald, & Cyster, 2017) but has not been tested in murine colitis.…”

Multiple Targets for Oxysterols in Their Regulation of the Immune System

“…GPR183 is also expressed on astrocytes and microglia in the brain, where it may thus effect neuroinflammatory diseases [55][56][57][58]. In the context of neuropathic pain, GPR183expressing astrocytes and microglia accumulate in the spinal cord and allodynic effects can be attenuated by the inhibition of this receptor in vivo [59].…”

Protein Tyrosine Phosphatase Receptor Type D Regulates Neuropathic Pain After Nerve Injury via the STING-IFN-I Pathway

“…Neuropathic pain is a type of chronic pain caused by injury or dysfunction of the somatosensory system and can dramatically influence the quality of the life of affected patients ( Baron et al, 2010 ; Cohen and Mao, 2014 ; Braden et al, 2020 ). Neuropathic pain is estimated to constitute a fifth of all chronic pain cases ( Fillingim et al, 2016 ; Bouhassira, 2019 ).…”