The Nociceptin/Orphanin FQ peptide receptor antagonist, SB-612111, improves cerebral blood flow in a rat model of traumatic brain injury

Abstract

Traumatic brain injury (TBI) affects more than 2.5 million people in the U.S. each year and is the leading cause of death and disability in children and adults ages 1 to 44. Approximately 90% of TBI cases are classified as mild but may still lead to acute detrimental effects such as impaired cerebral blood flow (CBF) that result in prolonged impacts on brain function and quality of life in up to 15% of patients. We previously reported that nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonism reversed mild blast TBI-induced vestibulomotor deficits and prevented hypoxia. To explore mechanisms by which the NOP receptor-N/OFQ pathway modulates hypoxia and other TBI sequelae, the ability of the NOP antagonist, SB-612111 (SB), to reverse TBI-induced CBF and associated injury marker changes were tested in this study. Male Wistar rats randomly received sham craniotomy or craniotomy + TBI via controlled cortical impact. Injury severity was assessed after 1 h (modified neurological severity score (mNSS). Changes in CBF were assessed 2 h post-injury above the exposed cortex using laser speckle contrast imaging in response to the direct application of increasing concentrations of vehicle or SB (1, 10, and 100 µM) to the brain surface. TBI increased mNSS scores compared to baseline and confirmed mild TBI (mTBI) severity. CBF was significantly impaired on the ipsilateral side of the brain following mTBI, compared to contralateral side and to sham rats. SB dose-dependently improved CBF on the ipsilateral side after mTBI compared to SB effects on the respective ipsilateral side of sham rats but had no effect on contralateral CBF or in uninjured rats. N/OFQ levels increased in the cerebral spinal fluid (CSF) following mTBI, which correlated with the percent decrease in ipsilateral CBF. TBI also activated ERK and cofilin within 3 h post-TBI; ERK activation correlated with increased CSF N/OFQ. In conclusion, this study reveals a significant contribution of the N/OFQ-NOP receptor system to TBI-induced dysregulation of cerebral vasculature and suggests that the NOP receptor should be considered as a potential therapeutic target for TBI.

Traumatic Brain Injury Induces Nociceptin/Orphanin FQ and Nociceptin Opioid Peptide Receptor Expression within 24 Hours

“…Though several previous TBI studies reported upregulation of the N/OFQ-NOP receptor system following TBI, none of them comprehensively examined protein, peptide, and mRNA level changes as a function of TBI severity [33,[35][36][37][38]. In this study, we report increases in N/OFQ levels in the injured brain tissue and CSF following mTBI and ModTBI on day 1 post-TBI in WT rats (Figure 2a,d).…”

“…The nociceptin opioid peptide (NOP) receptor, part of the opioid receptor superfamily [21][22][23][24][25][26][27], and its endogenous neuropeptide, N/OFQ, are widely expressed in the human body, including neurons, astrocytes, and microglia [28,29]. Acute increases in N/OFQ levels were found in cerebrospinal fluid (CSF) shortly after fluid percussion injury (FPI) [30][31][32] and CCI [33]. N/OFQ vasodilates cortical pial arteries under normal conditions but produces vasoconstriction following FPI and CCI [33][34][35].…”

“…Acute increases in N/OFQ levels were found in cerebrospinal fluid (CSF) shortly after fluid percussion injury (FPI) [30][31][32] and CCI [33]. N/OFQ vasodilates cortical pial arteries under normal conditions but produces vasoconstriction following FPI and CCI [33][34][35]. The vasoconstrictive action of N/OFQ was reversed by pretreatment with an NOP receptor antagonist [33] or partial agonist [35].…”

“…N/OFQ vasodilates cortical pial arteries under normal conditions but produces vasoconstriction following FPI and CCI [33][34][35]. The vasoconstrictive action of N/OFQ was reversed by pretreatment with an NOP receptor antagonist [33] or partial agonist [35]. Increases in brain tissue N/OFQ levels are found acutely following stab wound injury [36] and blast TBI (bTBI) [37] and sub-acutely post-CCI TBI in rats [38].…”

“…Increases in brain tissue N/OFQ levels are found acutely following stab wound injury [36] and blast TBI (bTBI) [37] and sub-acutely post-CCI TBI in rats [38]. The FPI, CCI, and bTBI studies implicated mitogen-activated protein kinases (MAPKs) in the cerebral vasoconstrictive effects of N/OFQ following TBI [33,37,39,40]. Though N/OFQ levels increased in ipsilateral brain tissue, 8 days post-CCI, they were unchanged in serum and CSF at that time [38].…”