The dynorphin/kappa opioid receptor mediates adverse immunological and behavioral outcomes induced by repetitive blast trauma

Journal of Neuroinflammation

Research

Britahny M. Baskin¹  Suhjung Janet Lee²  Mayumi Yagi²  Aric F. Logsdon³  David G. Cook⁴  Abigail. G. Schindler⁵  Elaine. R. Peskind⁶  Murray M. Raskind⁶ 

[1] Graduate Program in Neuroscience, University of Washington, 98195, Seattle, WA, USA;VA Northwest Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, S182, 1660 South Columbian Way, 98108, Seattle, WA, USA;VA Northwest Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, S182, 1660 South Columbian Way, 98108, Seattle, WA, USA;Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, 98195, Seattle, WA, USA;VA Northwest Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, S182, 1660 South Columbian Way, 98108, Seattle, WA, USA;Graduate Program in Neuroscience, University of Washington, 98195, Seattle, WA, USA;Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, 98195, Seattle, WA, USA;Department of Pharmacology, University of Washington, 98195, Seattle, WA, USA;VA Northwest Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, S182, 1660 South Columbian Way, 98108, Seattle, WA, USA;Graduate Program in Neuroscience, University of Washington, 98195, Seattle, WA, USA;Department of Psychiatry and Behavioral Sciences, University of Washington, 98195, Seattle, WA, USA;Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, 98195, Seattle, WA, USA;VA Northwest Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, 98108, Seattle, WA, USA;Department of Psychiatry and Behavioral Sciences, University of Washington, 98195, Seattle, WA, USA;

关键词: Blast overpressure;    Mild traumatic brain injury;    Posttraumatic stress disorder;    Kappa opioid receptor;    Dynorphin;    Cytokine;    Inflammation;   

DOI  :  10.1186/s12974-022-02643-3

 received in 2022-08-31, accepted in 2022-11-11,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundAdverse pathophysiological and behavioral outcomes related to mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and chronic pain are common following blast exposure and contribute to decreased quality of life, but underlying mechanisms and prophylactic/treatment options remain limited. The dynorphin/kappa opioid receptor (KOR) system helps regulate behavioral and inflammatory responses to stress and injury; however, it has yet to be investigated as a potential mechanism in either humans or animals exposed to blast. We hypothesized that blast-induced KOR activation mediates adverse outcomes related to inflammation and affective behavioral response.MethodsC57Bl/6 adult male mice were singly or repeatedly exposed to either sham (anesthesia only) or blast delivered by a pneumatic shock tube. The selective KOR antagonist norBNI or vehicle (saline) was administered 72 h prior to repetitive blast or sham exposure. Serum and brain were collected 10 min or 4 h post-exposure for dynorphin A-like immunoreactivity and cytokine measurements, respectively. At 1-month post-exposure, mice were tested in a series of behavioral assays related to adverse outcomes reported by humans with blast trauma.ResultsRepetitive but not single blast exposure resulted in increased brain dynorphin A-like immunoreactivity. norBNI pretreatment blocked or significantly reduced blast-induced increase in serum and brain cytokines, including IL-6, at 4 h post exposure and aversive/anxiety-like behavioral dysfunction at 1-month post-exposure.ConclusionsOur findings demonstrate a previously unreported role for the dynorphin/KOR system as a mediator of biochemical and behavioral dysfunction following repetitive blast exposure and highlight this system as a potential prophylactic/therapeutic treatment target.

【 授权许可】

CC BY   
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022

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