Development of a Small Chemical Drug That Targets EphB1 for the Treatment of Chronic Pain
Abstract
CPMRP Focus Areas: Development of novel non-Mu-opioid receptor-targeted therapies for the treatment of chronic pain, Novel non-opioid pharmacological solutions. Background and Relevance to Military Health: Chronic pain is a major problem for the military because many Soldiers become severely injured in the line of duty and an unfortunate long-term consequence of such trauma is often unresolved pain. Indeed, the number of prescriptions for pain medications written for military Service Members and Veterans has skyrocketed, and the Department of Veterans Affairs reports that chronic pain affects approximately half of Iraq- and Afghanistan-era Veterans seeking treatment. Despite these startling statistics, pain remains inadequately treated using drugs that may have tolerability and safety issues, including great potential for opioid abuse and addiction. Indeed, in an alarming fashion, opioids, both prescription painkillers (hydrocodone, oxycodone, morphine, and fentanyl) and illicit narcotics (heroin), are the main driver of drug overdose deaths in the United States, reaching epidemic levels and accounting for more deaths than from gun homicides. We must find ways to combat this opioid crisis and come up with new methods to treat those who suffer from pain that often leads them down the path of painkiller abuse. The problem is especially important from the military perspective considering the above-mentioned fact that Veterans are way more likely to suffer from chronic pain. Objective/Rationale/Hypothesis: Generally speaking, at the cellular level, chronic pain is caused by excessive injury-induced activation and firing of pain synapses in the peripheral nerves and spinal dorsal horn (DH) neurons, and this leads to persistent changes in the spinal cord, called plasticity, long-term potentiation (LTP), and central sensitization. These events ultimately lead to the development of chronic exaggerated pain, termed allodynia (pain due to a stimulus that does not usually provoke pain) and hyperalgesia (increased pain from a stimulus that usually provokes pain) that can affect the feelings of touch, pressure, pinprick, cold, and heat. One reason why current medications fail to adequately treat chronic pain is because they do not specifically home in and target the key signaling proteins in the DH neurons and associated sensory nerves that respond to nerve damage and alter the molecular/cellular plasticity pathways to generate LTP and cause central sensitization. Twelve years ago we first reported, using knockout mice made in the Principal Investigator’s laboratory, that the synaptic receptor protein EphB1 is essential for the formation of inflammatory and neuropathic pain caused by various forms of nerve injury/insult. Specifically, while the knockout mice lacking EphB1 receptor protein appear as typical long-lived animals that exhibit a normal sense of acute pain necessary for survival, when injured in various experimental models of chronic/neuropathic pain they do not go on to develop enhanced pain states when tested for thermal or mechanical pain. Electrophysiological experiments further showed that the DH neurons in the spinal cord of EphB1 knockout mice do not exhibit the typical LTP normally observed in wild-type mice following pain generating stimulations. This important work on knockout mice tells us that EphB1 is a central player needed for pain-mediated plasticity of DH neurons that generates chronic pain. It also leads to the hypothesis that small molecular weight drug-like chemicals can be identified that will block the activity of EphB1 protein and that such blocking compounds will have utility to prevent or reverse the development of hyperalgesia and allodynia following chronic pain-inducing insults. Research Plan: EphB1 is a transmembrane synaptic signaling receptor that is turned on when it binds to its cognate EphrinB ligand proteins. In the pain-sensing circuit, published data shows that nerve damage leads
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110949
Entities
People
- Mark Henkemeyer
Organizations
- United States Army
- University of Texas Southwestern Medical Center