Controlling Neuropathic Pain by Novel Nonopioid Pharmacological and Gene Therapeutic Approaches
Abstract
Chronic pain is a broadly experienced debilitating condition that represents a significant public health concern. The currently available options for the treatment and management of chronic pain are limited due to significant side effects of our most effective and most commonly used analgesics. The most effective pain relievers, opioids, are associated with risk of conversion to addiction and diversion from the patients for whom use is intended; these risks constitute a recognized national health problem and can cause tremendous human suffering. It has recently been recognized that military service personnel suffer greater chronic pain and potentially greater risks from opioid use than the general population. Within the last few years, the Department of Defense (DoD) and the Institute of Medicine (IoM) independently published important analyses on the state of chronic pain in the United States of America (USA). The IoM report is the source of the often cited values that 100 million U.S. adults are afflicted with chronic pain and that the national economic cost of chronic pain in the USA is estimated at $560-$635 billion/year. Through the DoD and the IoM reports, it is acknowledged that there is a great need for increased development of novel analgesics including non-opioid based medication. For nearly 20 years, our research group has investigated a mechanism in the central nervous system that inhibits the development and persistence of chronic pain and also reduces the development of opioid-induced tolerance, potentially reducing opioid dose requirements. This mechanism takes advantage of the communication system used by the amino acid glutamate, which carries the pain signal forward in the spinal cord. When the glutamate system is inhibited, chronic pain is reduced. There are several well-known clinically used drugs that can inhibit this system including dextromethorphan (an ingredient commonly found in cough syrup) and ketamine, an anesthetic. There have been attempts to develop both of these drugs to both treat chronic pain; however, they have other side effects that limit their use. We have studied the effects of a chemical related to the amino acid L-arginine, agmatine. We have shown that agmatine reduces chronic pain. Like dextromethorphan and ketamine, agmatine inhibits the glutamate system. The difference between agmatine and these other inhibitors of the glutamate system is that agmatine does not appear to have the same side effects as dextromethorphan and ketamine. Further, agmatine is a naturally produced compound, which opens up the possibility to develop a strategy using gene therapy to make agmatine in very specific regions where it is needed to control pain and potentially restrict it from regions where its action would result in undesirable effects. In this grant proposal, we would use two approaches to take advantage of these effects of agmatine. First, we would make agmatine-like chemicals with the goal of increasing the ability of agmatine to cross the blood-brain barrier. The chemistry of agmatine is such that it has some difficulty crossing the cells of blood vessels to enter the brain, a common problem with drugs. One way to improve that is to attach different chemicals to the main structure of agmatine that can improve its ability to cross. Once on the brain side, these chemicals are removed from agmatine so that it is available to exert its activity, for example, on chronic pain. The second approach is to insert the gene for the protein that makes agmatine into cells of the sensory system that code for pain. This strategy will make more agmatine directly in the region where pain is transmitted and potentially limit its distribution to other areas of the brain where it is not needed. A second approach we propose is to insert the gene into brain cells that secrete cerebrospinal fluid; this will enable a broader distribution of agmatine, which might be important for other type
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510494
Entities
People
- Carolyn A. Fairbanks
Organizations
- United States Army
- University of Minnesota