Pain in Gulf War Illness: Mechanisms and Candidate Treatments

Gulf War Illness (GWI) is an enigmatic syndrome affecting approximately 25-30% of those Veterans who served in the Gulf War. The origins of the syndrome remain undefined, although accumulating evidence suggests that exposure to certain chemicals and toxins including organophosphates, pyridostigmine, trace neurotoxins and combustion fumes leads to neuroinflammation in addition to persistent changes in the structure and function of the CNS and immune systems. Endogenous CNS regulatory centers may be particularly vulnerable. Furthermore, it is unclear why only a fraction of those exposed to Gulf War conditions have gone on to develop GWI. It is important, therefore, that cumulative effects of GWI-related chemical exposure additional stressors such as injuries and neuroinflammation be fully understood. Using well-characterized preclinical models, our overarching goal is to understand on behavioral, circuit, cellular and biochemical levels the interactions between chemical exposure neuroinflammation and injury contributing to the pain-related, functional, cognitive, mood and autonomic dimensions of GWI. We hypothesize that GWI-related chemical exposure produces neuroinflammation within the CNS thus worsening pain and function-related outcomes in models of clinically important pain states. Furthermore, we expect to observe that medications that augment pain regulatory centers may reduce pain-related and other GWI-like symptoms in preclinical models. The complementary skills of an established collaborative team will help us achieve our goals. The project approaches the central hypothesis using three aims. In the project’s first aim we focus on understanding the role of neuroinflammation in linking GWI chemical exposure to enhanced susceptibility to pain and other GWI-related outcomes. A well-characterized 4-chemical exposure model will be used alone or in combination with a joint injury procedure. Both pharmacologic agents and transgenic mice will be employed to regulate neuroinflammation. Pain, function, cognition and anxiety-related changes will be followed consistent with the principal complaints of GWI patients. Enhancing the impact of the aim, we will measure heart rate variability to detect autonomic changes consistent with the autonomic problems involved with GWI syndrome. The use of both sexes of mice enhances the rigor of the experimental design. The second aim attempts to determine whether neuroinflammation mediates the cellular and molecular consequences of GWI chemical exposure, joint injury. To be pursued in parallel to Aim 1, we have designed analyses directed at establishing the mechanistic basis of the GWI-related phenotypes. Experiments will focus on neuropathological studies of the regulatory centers of the brainstem and additional CNS structures implicated in GWI. We will carefully examine innate and adaptive immune functions, as these are suggested contributors to GWI as well. The collaborating laboratories have expertise required for all experiments. Finally, in the third aim we will determine whether inhibition of neuroinflammation preserves endogenous pain control systems. Translationally, we will assess the ability of an FDA-approved serotonin- norepinephrine reuptake inhibitor to reduce neuroinflammation as well as pain and functional changes after chemical exposure, joint injury or the combination of conditions. We hypothesize that restoration of dysfunctional endogenous pain modulation will be observed, and that additional component phenotypes will be responsive as well. The studies outlined in this proposal are of particularly high impact as we leverage expertise from multiple fields to address the origins of GWI-related symptoms using a range of approaches selected based on our emerging understanding of GWI. Our team is in excellent position to translate positive findings from the pharmacological studies to GWI patients at our VA medical center. Project Number: 1I01BX006217-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: DAVID CLARK (+1 co-PI) | Institution: VETERANS ADMIN PALO ALTO HEALTH CARE SYS, PALO ALTO, CA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 SPLD-T (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/10924609