Atypical Opioid Mechanisms of Control of Injury-Induced Cutaneous Pain by Delta Receptors
Abstract
Many military personnel return home from deployment with extensive combat-related injuries and associated pain. Combat-associated pain includes both acute pain, caused by the injuries themselves, and also chronic pain, which is broadly defined as pain that outlasts wound healing (>3 months). The prevalence of acute pain in combat-injured Service members in Iraq and Afghanistan was reported at 100%, and that of chronic pain in Operations Enduring Freedom and Iraqi Freedom (OIF/OEF) Veterans seeking medical care is estimated at 60%-80%. According to the Veterans Health Administration, 65% of OIF/OEF combat injuries are caused by improvised explosive devices, landmines, shrapnel, and other blast phenomena. Among the multiple types of injuries suffered most frequently by active military personnel are traumatic brain injury (TBI), nerve trauma, skin incision, and burn injury. Following injury, nerve fibers that innervate the skin are activated, causing acute pain sensation. Moreover, injured Soldiers often develop a state of hypersensitivity by which light touch (e.g., caress, wind blowing, clothing) generates excruciating pain. This chronic pain symptom, called mechanical allodynia or more simply touch-evoked pain, is common following TBI, burn, incision, or amputation and can persist for years following the injury, well beyond healing. Of particular interest are the studies that precisely characterized the types of pain caused by TBI, which indicate that touch-evoked pain was observed in 60% of patients with TBI. Pain experienced due to war-related injuries is difficult to treat, and some of our strongest drugs, such as morphine-like opioids, cause unacceptable side effects, including addiction. Clearly, effective and safer therapies to treat both acute and chronic pain among Soldiers and Veterans are urgently needed. The goal of this proposal is to advance the state of medical science in the area of severe acute and chronic pain management. We will evaluate a novel category of opioid analgesics that have a different mechanism of action than morphine, using rodent models of injuries that Soldiers can suffer on the battlefield, including burn, incisions, and nerve lesions. The compounds that we propose to test, named DOR agonists, act on nerve fibers in the skin and turn them off. Thus, we have collected impressive preliminary data that show that when we apply DOR agonists on skin, nerve fibers become silent and cannot transmit pain information to the brain where pain is normally perceived. Therefore, DOR agonists represent a very promising target for the development of new analgesics, to treat both acute pain, and chronic touch-evoked pain. Additionally, by contrast to morphine, which acts in the brain to provide pain relief but also to cause addiction, DOR agonists are unlikely to generate such side effects because they act on pain at its source (i.e., on nerve fibers, and not in the brain). We have assembled a strong team with unique basic science and clinical knowledge, experience, and research technical abilities to achieve this goal. Our proposal stems from years of research in the area of pain management and mechanisms of pain control, and from original preliminary data that identify DOR agonists as a remarkably promising target to treat pain caused by injuries. Few previous efforts have specifically focused drug development on local inactivation of skin nerve fibers to relieve pain from battlefield injury. Developing DOR agonists as topical analgesics would substantially advance our ability to provide pain relief to injured Soldiers, while eliminating addiction potential. It could represent a major step forward toward the translation of alternative opioid therapies that could be easily implemented on the battlefield and remote locations for severe acute pain management, as well as for the management of both acute and chronic pain in non-deployed settings. A large number of injured Soldiers and Vet
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510076
Entities
People
- Gregory Scherrer
Organizations
- Stanford University
- United States Army