title: Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder.
abstract: OBJECTIVE
  Single-prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), also induces long-lasting hyperalgesia associated with hypocortisolism and elevated nociceptin/orphanin FQ (N/OFQ) levels in serum and CSF. Here, we determined the effect of JTC-801 (N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist, on symptoms of pain and anxiety in rats after SPS exposure, and examined N/OFQ-NOP receptor system changes.
  
  
  METHODS
  Male Sprague Dawley rats received JTC-801 (6 mg kg(-1) i.p., once daily) during days 7-21 of SPS. The ability of JTC-801 to inhibit N/OFQ-stimulated [(35) S]-GTPγS binding was confirmed in rat brain membranes. Anxiety-like behaviour and pain sensitivity were monitored by changes in elevated plus maze performance and withdrawal responses to thermal and mechanical stimuli. Serum corticosterone and N/OFQ content in CSF, serum and brain tissues were determined by radioimmunoassay; NOP receptor protein and gene expression in amygdala, hippocampus and periaqueductal grey (PAG) were examined by immunoblotting and real-time PCR respectively.
  
  
  RESULTS
  JTC-801 treatment reversed SPS-induced mechanical allodynia, thermal hyperalgesia, anxiety-like behaviour and hypocortisolism. Elevated N/OFQ levels in serum, CSF, PAG and hippocampus at day 21 of SPS were blocked by JTC-801; daily JTC-801 treatment also reversed NOP receptor protein and mRNA up-regulation in amygdala and PAG.
  
  
  CONCLUSIONS
  JTC-801 reversed SPS-induced anxiety- and pain-like behaviours, and NOP receptor system up-regulation. These findings suggest that N/OFQ plays an important role in hyperalgesia and allodynia maintenance after SPS. NOP receptor antagonists may provide effective treatment for co-morbid PTSD and pain.
  
  
  BACKGROUND
  This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: C D
authors.initials: CD
authors.lastname: Simpson-Durand
authors.forename: K M
authors.initials: KM
authors.lastname: Standifer
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D018847:Opioid Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000235:genetics / Q000378:metabolism*; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy* / Q000378:metabolism; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000634:Aminoquinolines; D001549:Benzamides; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; C000722285:Oprl1 protein, rat
keywords: JTC-801; PTSD; allodynia; elevated plus maze; hypocortisolism; nociceptin/orphanin FQ; nociceptin/orphanin FQ peptide receptor; pain sensitivity; single-prolonged stress; von Frey test