Tumor Necrosis Factor‐alpha (TNFα) is Involved in the Initiation of Co‐morbid Allodynia and Anxiety in a Preclinical Post‐traumatic Stress Disorder (PTSD) Model
Authors: Standifer Kelly M , Zhang Yong 
Published: June 2021

Over 35% of people diagnosed with PTSD suffer from pain that significantly impacts their daily lives. PTSD is difficult to treat, and costs billions of dollars each year in lost wages and health care. The trigger for development of co‐morbid pain symptoms and anxiety in PTSD is unknown. We previously reported that rats develop tactile allodynia within days after exposure to the single prolonged stress (SPS) model of PTSD (sequential 2 hr restraint, 20 min forced group swim, ether anesthesia, and isolation), that lasts up to 28 days (Zhang et al., 2012; 2015). Serum TNFα levels significantly increased 4 hr post‐SPS and remained elevated through day 1 (p<0.001; N=6–15/group). Though serum TNFα was not elevated at 1 hr, TNFα mRNA from circulating blood cells was increased 6‐fold 1 hr post‐SPS (p<0.05). We hypothesized that TNFα initiates the development of allodynia following exposure to traumatic stress, and tested this using the SPS model. Rats were divided into 4 groups (N=5–6 rats per group) receiving normal goat IgG control (IgG) or rat TNFα antibody (anti‐TNFα) by tail vein (30 μg during the 1st two hr of the traumatic stress procedure in SPS and sham controls (Ctr). Hind paw nociceptive sensitivity was assessed on days 1, 3, and 7 with a digital von‐Frey probe (tactile allodynia) and Hargreaves apparatus (thermal hyperalgesia); anxiety‐like symptoms were measured by elevated plus maze on day 9. Rats were euthanized on day 9; serum, cerebrospinal fluid (CSF) and brains were extracted and flash frozen for analysis of nociceptin/orphanin FQ (N/OFQ). Data were analyzed by ANOVA with Tukey's multiple comparison test.ResultsRats in the SPS+IgG group were significantly more sensitive to paw pressure than rats in Ctr+IgG or Ctr+anti‐TNFα groups at day 3 and 7, whereas rats receiving SPS+anti‐TNFα did not exhibit allodynia (p<0.001). Similar results were obtained for thermal hyperalgesia (p<0.01) and anxiety index (p<0.01). SPS also increased N/OFQ levels at day 9 in brain and serum; anti‐TNFα treatment prevented N/OFQ increases in brain and serum (p<0.05).SummaryTreatment of rats with anti‐TNFα during traumatic stress prevented development of allodynia, hyperalgesia, anxiety‐like symptoms and elevated N/OFQ. These results support the hypothesis that acute elevation of serum TNFα in response to traumatic stress triggers the development of allodynia and anxiety‐like symptoms. We previously reported that SPS‐induced allodynia was reversed with N/OFQ peptide receptor (NOPr) antagonist. Since TNFα has been found to increase N/OFQ (Buzas et al., 2002), our results also suggest that subsequent increases of N/OFQ in serum and brain following traumatic stress may be mediated by TNFα. This work was conducted in conformance with the FASEB Statement of Principles for the use of Animals in Research and Education.Support or Funding InformationThe research results presented in this abstract were made possible in total or in part by funding for the award with project number HR17‐04, by the Oklahoma Center for the Advancement of Science and Technology, and by the Richard T. Anderson Chair in Neuroscience endowment.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.