Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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.

CONCLUSION AND IMPLICATIONS:

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.

LINKED ARTICLES:

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: Y Zhang, C D Simpson-Durand, K M Standifer
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 2 Pg. 571-82 (Jan 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 24666365 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Aminoquinolines
• Benzamides
• N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide
• Narcotic Antagonists
• Opioid Peptides
• Receptors, Opioid
• nociceptin
• Nociceptin Receptor
• Oprl protein, rat

Topics

• Aminoquinolines (pharmacology, therapeutic use)
• Amygdala (drug effects, metabolism)
• Animals
• Anxiety (drug therapy, metabolism)
• Benzamides (pharmacology, therapeutic use)
• Disease Models, Animal
• Hippocampus (drug effects, metabolism)
• Hot Temperature
• Hyperalgesia (drug therapy, metabolism)
• Male
• Narcotic Antagonists (pharmacology, therapeutic use)
• Opioid Peptides (blood, cerebrospinal fluid, metabolism)
• Pain (drug therapy, metabolism)
• Periaqueductal Gray (drug effects, metabolism)
• Rats, Sprague-Dawley
• Receptors, Opioid (genetics, metabolism)
• Stress Disorders, Post-Traumatic (drug therapy, metabolism)
• Nociceptin Receptor