Georgieva M, et al. - For the first time, researchers demonstrated that intravenous docosahexaenoic acid (DHA) administrations with 3-day intervals (250 nmol/kg; starting 30 minutes after injury and maintained for 6 weeks) is effective in preventing spinal cord injury (SCI)-central neuropathic pain (CNP) development in a clinically relevant rat contusion model. They assessed SCI-CNP using a novel sensory profiling approach joining evoked pain measures and pain-related ethologically relevant rodent behaviors (burrowing, thigmotaxis, and place/escape avoidance) to simulate those for measuring human (sensory, affective, cognitive, and spontaneous) pain. Strikingly, similar DHA administrations could lead to partial abolition of already established SCI-CNP, starting it from the beginning of week 4 after injury and maintained for 4 weeks. Microglial and astrocyte activation at spinal (epicenter and L5 dorsal horns) and supraspinal (anterior cingulate cortex) levels, which underpins SCI-CNP pathogenesis were potently suppressed with both treatment regimens. DHA treatments led to a reduction in spinal microgliosis, a known hallmark associated with neuropathic pain behaviors. Finally, novel potential roles of peroxisome proliferator–activated and retinoid X receptors and docosahexaenoyl ethanolamide (DHA's metabolite) were identified in mediating DHA's effects on microglial activation. These findings in combination with the excellent long-term clinical safety of DHA even in surgical and critically ill patients support that systemic DHA treatment is a translatable, efficient, safe, and novel approach for preventing and managing SCI-CNP.