title: Post-blast treatment with Nociceptin/Orphanin FQ peptide (NOP) receptor antagonist reduces brain injury-induced hypoxia and signaling proteins in vestibulomotor-related brain regions.
abstract: Mild traumatic brain injury (mTBI) diagnoses have increased due to aggressive sports and blast-related injuries, but the cellular mechanisms and pathology underlying mTBI are not completely understood. Previous reports indicate that Nociceptin Orphanin/FQ (N/OFQ), an endogenous neuropeptide, contributes to post-injury ischemia following mechanical brain injury, yet its specific role in cerebral hypoxia, vestibulomotor function and injury marker expression following blast-induced TBI is not known. This study is the first to identify a direct association of N/OFQ and its N/OFQ peptide (NOP) receptor with TBI-induced changes following a single 80psi head blast exposure in male rats. N/OFQ and NOP receptor expression increased in brain tissue and plasma following TBI, concurrent with vestibular dysfunction but preceding hypoxia and appearance of injury markers compared to sham rats. A single post-blast treatment with the NOP receptor antagonist, SB-612111, transiently improved acute vestibulomotor performance. It also prevented increases in markers of TBI-induced hypoxia, pro-apoptotic proteins and injury seen 8-10days post-blast. This study reveals an apparent role for the N/OFQ-NOP receptor system in blast TBI and suggests potential therapeutic utility of NOP receptor antagonists for mTBI.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, Oklahoma City, OK, USA. Electronic address: hawwad@ouhsc.edu.
authors: Hibah O
authors: HO
authors: Awwad
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors: Cindy D
authors: CD
authors: Durand
authors: Oklahoma Center for Neuroscience, Oklahoma City, OK, USA; Department of Psychiatry & Behavioral Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors: Larry P
authors: LP
authors: Gonzalez
authors: Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors: Paul
authors: P
authors: Tompkins
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, Oklahoma City, OK, USA.
authors: Yong
authors: Y
authors: Zhang
authors: Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA; Oklahoma city VA Medical Center, Oklahoma City, OK 73117, USA.
authors: Megan R
authors: MR
authors: Lerner
authors: Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA.
authors: Daniel J
authors: DJ
authors: Brackett
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, Oklahoma City, OK, USA; Department of Cell Biology, College of Medicine, University of Oklahoma Health Sciences Center, USA.
authors: David M
authors: DM
authors: Sherry
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors: Vibhudutta
authors: V
authors: Awasthi
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, Oklahoma City, OK, USA; Department of Cell Biology, College of Medicine, University of Oklahoma Health Sciences Center, USA.
authors: Kelly M
authors: KM
authors: Standifer
mesh_terms: D000818:Animals; D001753:Blast Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001924:Brain Concussion / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D003508:Cycloheptanes / Q000494:pharmacology*; D002534:Hypoxia, Brain / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009292:Narcotic Antagonists / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D020543:Proteome / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: D003508:Cycloheptanes; D009292:Narcotic Antagonists; D018696:Neuroprotective Agents; D010880:Piperidines; D020543:Proteome; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; C000722285:Oprl1 protein, rat
keywords: Blast traumatic brain injury; Hypoxia; Nociceptin/Orphanin FQ peptide receptor; PET imaging; Rotarod; Vestibulomotor