Alleviation of Chronic Neuropathic Pain by Agmatine Requires the GluN2B Subunit of the NMDA Receptor

Abstract

Effective treatment for chronic pain patients remains an area of largely unmet need. However, chronic pain patients receiving traditional opioid therapy are consistently surrounded by the potential risks and social stigmas of opioid dependence, misuse, and addiction. These concerns are heightened in the face of the expanding opioid epidemic. The need for new, non-opioidergic therapeutics for management of the large population of chronic patients is widely recognized. Agmatine, also known as decarboxylated arginine, is an endogenous small molecule that has been shown to modulate maladaptive neuroplasticity that underlies the experience of chronic pain. Agmatine has been established to meet the criteria of acting as a neurotransmitter including synthesis in neurons, release from nerve terminals, and binding to post-synaptic receptors. We have previously demonstrated the efficacy of exogenously delivered agmatine in reversing chronic pain behaviors in models of neuropathic pain. Targeting primary sensory neurons through gene vectors such as serotypes of the adeno-associated virus has recently been identified as a powerful emerging strategy to treat chronic, intractable pain. Gene therapy has been approved for market use in Europe and the United States, making it a viable tool for translation from bench side to clinic. To this end, a viral vector encoding the synthetic enzyme for agmatine, namely arginine decarboxylase was developed. It has been shown that intrathecally injected viral vector particles distribute to sites of interest for chronic pain. The primary objective of my thesis work has been to expand both the application and mechanistic understanding of agmatine as a non-opioidergic therapeutic in the treatment of chronic pain. The central hypothesis of this work is that enhanced expression of arginine decarboxylase in nociceptive pathways results in long-term reduction of neuropathic pain due to agmatine production and agmatine’s antagonism of the NMDA receptor. The rationale for this research was that delivery of a gene therapy to enhance agmatine’s inhibition of NMDA signaling would be a viable, long term solution for management of chronic pain. In this thesis, I will expand upon the dual public health crises of chronic pain and prescription opioid abuse. These call for new, non-opioid therapeutic approaches for chronic pain, leading to the therapeutic development of agmatine as an NMDA receptor antagonist.