Post-blast treatment with Nociceptin/Orphanin FQ peptide (NOP) receptor antagonist reduces brain injury-induced hypoxia and signaling proteins in vestibulomotor-related brain regions.

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.

Blast Overpressure Waves Induce Transient Anxiety and Regional Changes in Cerebral Glucose Metabolism and Delayed Hyperarousal in Rats.

Physiological alterations, anxiety, and cognitive disorders are strongly associated with blast-induced traumatic brain injury (blast TBI), and are common symptoms in service personnel exposed to blasts. Since 2006, 25,000-30,000 new TBI cases are diagnosed annually in U.S. Service members; increasing evidence confirms that primary blast exposure causes diffuse axonal injury and is often accompanied by altered behavioral outcomes. Behavioral and acute metabolic effects resulting from blast to the head in the absence of thoracic contributions from the periphery were examined, following a single blast wave directed to the head of male Sprague-Dawley rats protected by a lead shield over the torso. An 80 psi head blast produced cognitive deficits that were detected in working memory. Blast TBI rats displayed increased anxiety as determined by elevated plus maze at day 9 post-blast compared to sham rats; blast TBI rats spent significantly more time than the sham controls in the closed arms (p < 0.05; n = 8-11). Interestingly, anxiety symptoms were absent at days 22 and 48 post-blast. Instead, blast TBI rats displayed increased rearing behavior at day 48 post-blast compared to sham rats. Blast TBI rats also exhibited suppressed acoustic startle responses, but similar pre-pulse inhibition at day 15 post-blast compared to sham rats. Acute physiological alterations in cerebral glucose metabolism were determined by positron emission tomography 1 and 9 days post-blast using (18)F-fluorodeoxyglucose ((18)F-FDG). Global glucose uptake in blast TBI rat brains increased at day 1 post-blast (p < 0.05; n = 4-6) and returned to sham levels by day 9. Our results indicate a transient increase in cerebral metabolism following a blast injury. Markers for reactive astrogliosis and neuronal damage were noted by immunoblotting motor cortex tissue from day 10 post-blast in blast TBI rats compared to sham controls (p < 0.05; n = 5-6).

Brain injury: neuro-inflammation, cognitive deficit, and magnetic resonance imaging in a model of blast induced traumatic brain injury.

Blast wave-induced traumatic injury from terrorist explosive devices can occur at any time in either military or civilian environments. To date, little work has focused on the central nervous system response to a non-penetrating blast injury. We have evaluated the effect of a single 80-psi blast-overpressure wave in a rat model. Histological and immunochemical studies showed an early inflammatory response, tissue damage and the initiation of apoptosis. With regard to inflammation, polymorphonuclear leukocytes and lymphocytes infiltrated brain parenchyma within 1 h post-blast. Glial-fibrillary protein, cyclo-oxygenase-2ir, interleukin-1ß and tumor necrosis factor were present by 1 h and remained detectable at three weeks post-injury. High mobility group box-1 protein was detectable at three weeks. With regard to tissue damage, S100ß and 4-hydroxynonenal were present at 1 h and remained detectable at three weeks. Amyloid precursor protein was detectable at three weeks. As for apoptosis, Cleaved Caspase-3 was detectable at three weeks. Morris water maze assessment of cognitive function showed that blast injured animals required significantly more time to reach the platform on day 1 of training and traveled a greater distance to get to the platform on days 1 and 2. Blast-injured animals showed a significant increase in swimming speed (p<0.001), increased total distance traveled (p<0.001) and increased number of entries into the previous quadrant that had contained the escape platform (p<0.05). Magnetic resonance imaging showed hyperintense regions in the somatosensory area within 1 h. T2 relaxation times and apparent diffusion coefficients show increasing trends in both somatosensory and cortical regions. These data indicate an early and lasting response of brain tissue to non-penetrating blast over-pressure injury. This early inflammatory response is indicative of a mild traumatic brain injury. There is evidence of early hippocampal dysfunction.

Integrative neurobiology of the alcohol withdrawal syndrome--from anxiety to seizures.

This article represents the proceedings of a symposium presented at the 2003 Research Society on Alcoholism meeting in Ft. Lauderdale, Florida, organized and chaired by Carl L. Faingold. The presentations were (1) Overview, by Carl L. Faingold; (2) Stress, Multiple Alcohol Withdrawals, and Anxiety, by Darin Knapp; (3) Relationship Between Genetic Differences in Alcohol Drinking and Alcohol Withdrawal, by Julia Chester; (4) Neuronal Mechanisms in the Network for Alcohol Withdrawal Seizures: Modulation by Excitatory Amino Acid Receptors, by Carl L. Faingold; and (5) Treatment of Acute Alcohol Withdrawal and Long-Lasting Alterations in Hippocampal Neuronal Networks, by Larry P. Gonzalez. The presentations emphasized the importance of using intact behaving animals to advance the understanding of the human alcohol withdrawal syndrome. This involves applying and amplifying the neurophysiological and neurotransmitter findings observed in vitro to the network-based neurobiological mechanisms that are involved in several important aspects of the specific behaviors observed clinically. The symposium provided evidence that the organizational aspects of neuronal networks in the intact nervous system add another nexus for the action of alcohol and drugs to treat alcohol withdrawal that may not be readily studied in isolated neural elements used in in vitro approaches.