Loss of Nociceptin/Orphanin FQ peptide receptor protects against traumatic brain injury (TBI)‐induced deficits in male and female rats

Abstract

Introduction : Traumatic brain injury (TBI) is a leading cause of death and disability in the United States and often chronically affects mental and physical health and overall quality of life. We previously reported that acute treatment of blast TBI with a Nociceptin/OrphaninFQ (N/OFQ) peptide receptor (NOP) antagonist improved vestibulomotor deficits in male rats, corresponding to TBI-induced increases in NOP and its endogenous neuropeptide N/OFQ. The goal of this study is to determine whether the absence of NOP protects against neurological and behavioral sequelae of TBI in male and female KO rats compared to WT. Methods Male and female Wistar NOP receptor knockout (NOP KO) and wildtype (WT) rats received either a sham craniotomy, mild TBI (mTBI) or moderate TBI (ModTBI) controlled cortical impact (CCI) to the left cerebral hemisphere. Injury severity and recovery were assessed using modified neurological severity score (mNSS) on days 1 and 8 post-TBI. Vestibulomotor function was determined using the rotarod. Nociceptive sensitivity to mechanical and thermal stimuli were determined by measuring hind paw withdrawal threshold (PWT) to plastic filaments and by measuring tail flick latency (TFL) from radiant heat, respectively, prior to injury (baseline) and on days 2, 4, and 7 post-TBI. The presence of anxiety-like symptoms was assessed using the elevated plus maze (EPM) on day 7 post-TBI. Data were analyzed by two-way ANOVA with or without repeated measures (as appropriate). Results Rats of both genotypes and sexes showed complete neurological recovery (mNSS<1) following mTBI, and partial recovery following ModTBI by day 8. Mild and ModTBI produced significant vestibular deficits in rat rotarod performance on days 1-8 post-TBI in WT male (n=7-8). In WT females (n=8), ModTBI produced vestibular deficits on days 1-7, whereas mTBI only produced vestibular deficits on days 1-4. Interestingly, neither male (n=5-6) nor female (n=3) mTBI NOP KO rats exhibited vestibulomotor deficits. ModTBI caused significant vestibular deficits only on day 1 post-TBI in male and female NOP KO rats. Rotarod performance in WT females was significantly worse than KO females on days 2-4 post TBI following moderate injury (*p<0.05), and on days 4-7 following mild injury (*p<0.05). WT males (n=7-8) and females (n=8) exhibited thermal hyperalgesia and mechanical allodynia throughout the study, with little difference between mild and moderate TBI groups. KO males (n=3) developed no thermal hyperalgesia after either mild or ModTBI. Only ModTBI rats developed mechanical allodynia, and it lasted throughout the study. KO females (n=3) showed both thermal and mechanical hypersensitivity on day 2 and only mechanical hypersensitivity on day 4. No differences in anxiety-like behaviors were found between any of the groups. Conclusion The N/OFQ-NOP system contributes to vestibular deficits and hyperalgesia associated with TBI; the absence of NOP protects against TBI-induced vestibulomotor deficits and nociceptive hypersensitivity.