Enhanced descending pain facilitation in acute traumatic brain injury

• Published in: Experimental neurology Vol. 320; p. 112976
• Main Authors: Irvine, Karen-Amanda, Sahbaie, Peyman, Ferguson, Adam R., Clark, J. David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019
• Subjects: Acute brain injury; Animals; Brain Injuries, Traumatic - complications; Brain Injuries, Traumatic - physiopathology; Hyperalgesia - etiology; Hyperalgesia - physiopathology; Male; Neuroinflammation; Ondansetron - pharmacology; Pain; Pain - etiology; Pain - physiopathology; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin 5-HT3 Receptor Antagonists - pharmacology; Spinal Cord - drug effects; Spinal Cord - metabolism; CPM; TNFα; DH; DNIC; RVM; CNS; IBA-1; Pain; LFP; TBI; PBS; Serotonin; DAB; BDNF; L4; Neuroinflammation; IL-1β; NGF; PWT; 5-HTR; GFAP; AR; CT; 5, 7-DHT/DHT; LC; PAG; VEH; Acute brain injury; SEM; Atm; 5-HT; DPI
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2019.112976

Acute and persistent pain are recognized consequences of TBI that can enhance suffering and significantly impair rehabilitative efforts. Both experimental models and clinical studies suggest that TBI may result in an imbalance between descending pain facilitatory and inhibitory pathways. The aim of this study was to assess the role of enhanced descending serotonin-mediated pain facilitation in a rat TBI model using selective spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine (DHT). We observed significant hindpaw allodynia in TBI rats that was reduced after DHT but not vehicle treatment. Immunohistochemical studies demonstrated profound spinal serotonin depletion in DHT-treated rats. Furthermore, lumbar intrathecal administration of the 5-HT3 receptor antagonist ondansetron at 7 days post-injury (DPI), when hindpaw allodynia was maximal, also attenuated nociceptive sensitization. Additional immunohistochemical analyses of the lumbar spinal cord at 7 DPI revealed a robust bilateral microglial response in the superficial dorsal horns that was significantly reduced with DHT treatment. Furthermore, serotonin depletion also prevented the TBI-induced bilateral increase in c-Fos positive cells within the Rexed laminae I and II of the dorsal horns. These results indicate that in the weeks following TBI, pain may be responsive to 5-HT3 receptor antagonists or other measures which rebalance descending pain modulation. •TBI patients frequently experience high rates of acute and chronic pain.•Pain after TBI is likely due to an imbalance in the descending pain modulatory (facilitatory versus inhibitory) pathways.•Reducing 5-HT-mediated pain facilitation via spinal 5,7-DHT decreased hindpaw allodynia after TBI.•Ondansetron treatment suggests 5-HT3R signaling has a role in enhanced descending pain facilitation after TBI.•5,7-DHT treatment decreased the TBI-induced increase in the microglial response and neuronal activation in the spinal cord.