Exacerbated Headache‐Related Pain in the Single Prolonged Stress Model of Post‐traumatic Stress Disorder

Abstract

Post‐traumatic stress disorder (PTSD) frequently shares co‐morbidity with chronic pain and negatively impacts the course of treatment for both disorders. Single‐prolonged stress (SPS), an established animal model for PTSD, models many of the symptoms of PTSD reported in humans including exaggerated negative feedback of the HPA axis, hypocortisolism, enhanced fear and anxiety responses and cognitive impairment. We and others reported that SPS induces long‐lasting mechanical and thermal allodynia and visceral and inflammatory hypersensitivity. Chronic headache pain is one of the most commonly reported co‐morbid pain conditions by PTSD patients and one of the most resistant to effective treatment, yet this has never been modeled in an animal model of PTSD. We modified the chronic headache pain model recently developed by Pradhan and colleagues (2014) to investigate the contribution of SPS to sodium nitroprusside (SNP)‐induced hyperalgesia. SPS and control Sprague Dawley rats were randomly divided into SNP or vehicle‐treated groups. SNP (2 mg/kg, i.p.) was injected every second day from day 7 to 15 after initiation of SPS. Rat paw withdrawal threshold (PWT) to von Frey stimuli and tail flick latencies (TFL) dramatically decreased as early as 7 days after SPS and lasted until at least day 21. Basal PWT and TFL, as assessed prior to each SNP administration, also significantly decreased during the SNP treatment period. The lower pain thresholds recovered 7 days following the final SNP injection in SNP group, but not in SPS/SNP group. Nociceptin/orphanin FQ (N/OFQ) plays an important role in maintenance of hyperalgesia and allodynia following SPS. Elevated N/OFQ levels observed in cerebrospinal fluid (CSF) of SPS rats were even higher in CSF of the SPS/SNP group. Real‐time PCR revealed that glial fibrillary acidic protein (GFAP) and N/OFQ peptide (NOP) receptor mRNA expression increased in dorsal root ganglia (DRG) 21 days after SPS exposure; mRNA increases in the SPS/SNP group was more pronounced than SPS or SNP alone. PreproN/OFQ mRNA expression decreased in both SPS and SPS/SNP rats compared to control, but no difference was observed between the two groups. SNP treatment alone did not alter GFAP, NOP receptor or N/OFQ mRNA levels in DRG. Significant interaction between SNP and SPS was noted following immunoblot analysis of TNF alpha protein expression in DRG and NOP receptor expression in trigeminal ganglia. Our results indicate that chronic SNP‐induced nociceptive hypersensitivity (headache pain) is exaggerated in rats exposed to PTSD, and that N/OFQ may play an important role in the interaction between SPS and SNP.The animal protocol was approved by the OUHSC IACUC committee; studies conformed to the FASEB Statement of Principles for the use of animals in research and education.Support or Funding InformationUniversity of Oklahoma Health Sciences Center Vice President for Research and Presbyterian Health Foundation Bridge Grant Programs.