The GLUN2B subunit of the NMDA receptor as an effector of inhibitory and pro-nociceptive neuromodulators

Abstract

Chronic pain affects over 20% of adults in the U.S., imposing a significant personal and economic burden, while most existing therapies are not suitable for long-term use. Chronic pain patients critically need an alternative effective treatment with minimal side effects. To create such treatments, it is essential to understand the pain circuitry and different mechanisms of how chronic pain can develop. One promising therapeutic target is the GluN2B-containing NMDA receptor in the spinal cord dorsal horn. Antagonizing this receptor has been shown to prevent the development of central sensitization, a key driver of chronic pain. Building on the understanding of NMDA receptors, this thesis described both pronociceptive and inhibitory modulation of spinal GluN2B-NMDA receptors using a novel NMDA-evoked calcium response assay in the mouse spinal cord dorsal horn. The results showed that the spinal NMDA receptor mediates the maladaptive involvement of the VGF-derived peptide TLQP-62. In contrast, the inhibitory effects of agmatine on spinal NMDA receptor activity require intact spinal PSD95-nNOS tethering. While further research is required to fully characterize the direct interactions of these modulators with NMDA receptors, it is hoped that this study will help the goal of developing safe and effective therapeutics for pain patients.