The NMDAR modulator NYX-2925 alleviates neuropathic pain via a Src-dependent mechanism in the mPFC

Gladys Morrison,Marina N Asiedu,Jessica M Priebe,Jacqueline Dunning,Nayereh Ghoreishi-Haack,Roger A Kroes,M Scott Bowers,Amanda L Barth,Cassia N Cearley,Joseph R Moskal

doi:10.1016/j.ynpai.2019.100039

Gladys Morrison, Marina N Asiedu + Show 8 more

Open Access

https://doi.org/10.1016/j.ynpai.2019.100039

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Abstract

Previous studies have shown that oral administration of the NMDAR modulator NYX-2925 alleviates pain in several animal models of neuropathic pain and this appears to be through mPFC, but not spinal, mediated mechanisms. While much is known about the impact of neuropathic pain on NMDAR-mediated signaling in the spinal cord, limited studies have focused on the brain. In the current study, we assess signaling changes associated with NMDAR-mediated plasticity in the mPFC and the impact of NYX-2925 administration on the normalization of these signaling changes. We found a decrease in activated Src levels in the mPFC of animals with chronic constriction injury (CCI) of the sciatic nerve. While Src mediated activation of NMDARs was also decreased in CCI animals, the main NMDAR phosphorylation site of CAMKII was not affected. This is in opposition to what has been found in the spinal cord, where both Src and CAMKII activation are increased. Oral administration of NYX-2925 restored levels of activated Src and Src phosphorylation sites on GluN2A and GluN2B in the mPFC, with no effect on activated CAMKII levels. The analgesic effect of NYX-2925 appears dependent on this restoration of Src activation in the mPFC, as co-administering Src activation inhibitors prevented the NYX-2925 analgesic effect. Overall, these data suggest that NMDAR-mediated signaling plays a key role in neuropathic pain, albeit in different directions in the spinal cord vs. the mPFC. Furthermore, the analgesic effect of NYX-2925 appears to involve a restoration of NMDAR-mediated signaling in the mPFC.

Highlights

Chronic neuropathic pain is a disease resulting from long-term changes to synaptic plasticity mechanisms in the spinal cord (Costigan et al, 2009; Woolf and Salter, 2000), as well as in subcortical and cortical areas (Zhuo, 2008; Zhuo, 2018)
N-methyl-D-aspartate receptor (NMDAR) canonical Src family kinase sites are differentially regulated by constriction injury (CCI)-induced neuropathic pain and NYX-2925
Pain induced changes in NMDAR levels and associated kinases in the medial prefrontal cortex (mPFC) were investigated in SHAM controls, vehicle-treated CCI rats, and NYX-2925-treated CCI rats

Summary

Introduction

Chronic neuropathic pain is a disease resulting from long-term changes to synaptic plasticity mechanisms in the spinal cord (Costigan et al, 2009; Woolf and Salter, 2000), as well as in subcortical and cortical areas (Zhuo, 2008; Zhuo, 2018). Preclinical studies have shown overall reduced activity of the prelimbic mPFC in neuropathic pain that appears to result from impaired glutamatergic transmission (Kelly et al, 2016). This reduction in mPFC activity is implicated in affective and cognitive changes associated with chronic pain (Millecamps et al, 2007; Wang et al, 2015). In the rat chronic constrictive injury (CCI) model of neuropathic pain, intrathecal injection of NYX-2925 had no therapeutic effect, while systemic administration or direct infusion of NYX-2925 into the mPFC alleviated neuropathic pain (Ghoreishi-Haack et al, 2018) These data suggested that NYX-2925 may be acting in the brain, with direct activity in the mPFC, to alleviate neuropathic pain

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