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Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder.
Br J Pharmacol 2015; 172(2):571-82BJ

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+Show Affiliations

Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

24666365

Citation

Zhang, Y, et al. "Nociceptin/orphanin FQ Peptide Receptor Antagonist JTC-801 Reverses Pain and Anxiety Symptoms in a Rat Model of Post-traumatic Stress Disorder." British Journal of Pharmacology, vol. 172, no. 2, 2015, pp. 571-82.
Zhang Y, Simpson-Durand CD, Standifer KM. Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder. Br J Pharmacol. 2015;172(2):571-82.
Zhang, Y., Simpson-Durand, C. D., & Standifer, K. M. (2015). Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder. British Journal of Pharmacology, 172(2), pp. 571-82. doi:10.1111/bph.12701.
Zhang Y, Simpson-Durand CD, Standifer KM. Nociceptin/orphanin FQ Peptide Receptor Antagonist JTC-801 Reverses Pain and Anxiety Symptoms in a Rat Model of Post-traumatic Stress Disorder. Br J Pharmacol. 2015;172(2):571-82. PubMed PMID: 24666365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder. AU - Zhang,Y, AU - Simpson-Durand,C D, AU - Standifer,K M, Y1 - 2014/07/01/ PY - 2013/11/04/received PY - 2014/03/17/revised PY - 2014/03/20/accepted PY - 2014/3/27/entrez PY - 2014/3/29/pubmed PY - 2015/9/12/medline KW - JTC-801 KW - PTSD KW - allodynia KW - elevated plus maze KW - hypocortisolism KW - nociceptin/orphanin FQ KW - nociceptin/orphanin FQ peptide receptor KW - pain sensitivity KW - single-prolonged stress KW - von Frey test SP - 571 EP - 82 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 172 IS - 2 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/24666365/Nociceptin/orphanin_FQ_peptide_receptor_antagonist_JTC_801_reverses_pain_and_anxiety_symptoms_in_a_rat_model_of_post_traumatic_stress_disorder_ DB - PRIME DP - Unbound Medicine ER -