Huy Nguyen1, Peyman Sahbaie2, Lihle Goba3, Julian Sul4, Aoi Suzaki4, J David Clark5, Ting-Ting Huang6. 1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, United States of America; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, United States of America; Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, United States of America. 2. Department of Anesthesiology, Stanford University School of Medicine, United States of America; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, United States of America; Anesthesiology Service, VA Palo Alto Health Care System, United States of America. 3. Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, United States of America. 4. Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, United States of America. 5. Department of Anesthesiology, Stanford University School of Medicine, United States of America; Anesthesiology Service, VA Palo Alto Health Care System, United States of America. 6. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, United States of America; Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, United States of America. Electronic address: tthuang@stanford.edu.
Abstract
AIMS: A substantial contingent of veterans from the first Gulf War continues to suffer from a number of Gulf War-related illnesses (GWI) affecting the neurological and musculoskeletal systems; the most common symptoms include chronic pain and fatigue. Although animal models have recapitulated several aspects of cognitive impairments in GWI, the pain and fatigue symptoms have not been well documented to allow examination of potential pathogenic mechanisms. MAIN METHODS: We used a mouse model of GWI by exposing mice repeatedly to a combination of Gulf War chemicals (pyridostigmine bromide, permethrin, DEET, and chlorpyrifos) and mild immobilization stress, followed by investigating their pain susceptibilities and fatigue symptoms. To assess whether enhanced antioxidant capacity can counter the effects of GW agents, transgenic mice overexpressing extracellular superoxide dismutase (SOD3OE) were also examined. KEY FINDINGS: The mouse model recapitulated several aspects of the human illness, including hyperalgesia, impaired descending inhibition of pain, and increased tonic pain. There is a close association between chronic pain and fatigue in GWI patients. Consistent with this observation, the mouse model showed a significant reduction in physical endurance on the treadmill. Examination of skeletal muscles suggested reduction in mitochondrial functions may have contributed to the fatigue symptoms. Furthermore, the negative impacts of GW agents in pain susceptibilities were largely diminished in SOD3OE mice, suggesting that increased oxidative stress was associated with the emergence of these Gulf War symptoms. SIGNIFICANCE: the mouse model will be suitable for delineating specific defects in the pain pathways and mechanisms of fatigue in GWI.
AIMS: A substantial contingent of veterans from the first Gulf War continues to suffer from a number of Gulf War-related illnesses (GWI) affecting the neurological and musculoskeletal systems; the most common symptoms include chronic pain and fatigue. Although animal models have recapitulated several aspects of cognitive impairments in GWI, the pain and fatigue symptoms have not been well documented to allow examination of potential pathogenic mechanisms. MAIN METHODS: We used a mouse model of GWI by exposing mice repeatedly to a combination of Gulf War chemicals (pyridostigmine bromide, permethrin, DEET, and chlorpyrifos) and mild immobilization stress, followed by investigating their pain susceptibilities and fatigue symptoms. To assess whether enhanced antioxidant capacity can counter the effects of GW agents, transgenic mice overexpressing extracellular superoxide dismutase (SOD3OE) were also examined. KEY FINDINGS: The mouse model recapitulated several aspects of the human illness, including hyperalgesia, impaired descending inhibition of pain, and increased tonic pain. There is a close association between chronic pain and fatigue in GWI patients. Consistent with this observation, the mouse model showed a significant reduction in physical endurance on the treadmill. Examination of skeletal muscles suggested reduction in mitochondrial functions may have contributed to the fatigue symptoms. Furthermore, the negative impacts of GW agents in pain susceptibilities were largely diminished in SOD3OE mice, suggesting that increased oxidative stress was associated with the emergence of these Gulf War symptoms. SIGNIFICANCE: the mouse model will be suitable for delineating specific defects in the pain pathways and mechanisms of fatigue in GWI.